Aryl sulfonamides

ABSTRACT

Compounds are provided that act as potent antagonists of the CCR9 receptor, and which have been further confirmed in animal testing for inflammation, one of the hallmark disease states for CCR9. The compounds are generally aryl sulfonamide derivatives and are useful in pharmaceutical compositions, methods for the treatment of CCR9-mediated diseases, and as controls in assays for the identification of CCR9 antagonists.

RELATED APPLICATIONS

[0001] This application claims priority to U.S. provisional applicationSerial No. 60/427,670 filed Nov. 18, 2002. The disclosure of thepriority application is incorporated by reference herein in itsentirety.

BACKGROUND OF THE INVENTION

[0002] The present invention provides compounds, pharmaceuticalcompositions containing one or more of those compounds or theirpharmaceutically acceptable salts, which are effective in inhibiting thebinding or function of various chemokines, such TECK, to the CCR9receptor. As antagonists or modulators for the CCR9 receptor, thecompounds and compositions have utility in treating inflammatory andimmune disorder conditions and diseases.

[0003] Chemokines are chemotactic cytokines that are released by a widevariety of cells and attract various types of immune system cells, suchas macrophages, T cells, eosinophils, basophils and neutrophils, tosites of inflammation (reviewed in Schall, Cytokine, 3:165-183 (1991),Schall, et al., Curr. Opin. Immunol., 6:865 873 (1994) and Murphy, Rev.Immun., 12:593-633 (1994)). In addition to stimulating chemotaxis, otherchanges can be selectively induced by chemokines in responsive cells,including changes in cell shape, transient rises in the concentration ofintracellular free calcium ions ([Ca²⁺]), granule exocytosis, integrinup-regulation, formation of bioactive lipids (e.g., leukotrienes) andrespiratory burst, associated with leukocyte activation. Thus, thechemokines are early triggers of the inflammatory response, causinginflammatory mediator release, chemotaxis and extravasation to sites ofinfection or inflammation.

[0004] T lymphocyte (T cell) infiltration into the small intestine andcolon has been linked to the pathogenesis of Coeliac diseases, foodallergies, rheumatoid arthritis, human inflammatory bowel diseases (IBD)which include Crohn's disease and ulcerative colitis. Blockingtrafficking of relevant T cell populations to the intestine can lead toan effective approach to treat human IBD. More recently, chemokinereceptor 9 (CCR9) has been noted to be expressed on gut-homing T cellsin peripheral blood, elevated in patients with small bowel inflammationsuch as Crohn's disease and celiac disease. The only CCR9 ligandidentified to date, TECK (thymus-expressed chemokine) is expressed inthe small intestine and the ligand receptor pair is now thought to playa pivotal role in the development of IBD. In particular, this pairmediates the migration of disease causing T cells to the intestine. Seefor example, Zaballos, et al., J. Immunol., 162(10):5671-5675 (1999);Kunkel, et al., J. Exp. Med. 192(5):761-768 (2000); Papadakis, et al.,J. Immunol., 165(9):5069-5076 (2000); Papadakis, et al.,Gastroenterology, 121(2):246-254 (2001); Campbell, et al., J. Exp. Med.,195(1):135-141 (2002); Wurbel, et al., Blood, 98(9):2626-2632 (2001);and Uehara, et al., J. Immunol, 168(6):2811-2819 (2002).

[0005] The identification of compounds that modulate the function ofCCR9 represents an attractive new family of therapeutic agents for thetreatment of inflammatory and other conditions and diseases associatedwith CCR9 activation, such as inflammatory bowel disease.

BRIEF SUMMARY OF THE INVENTION

[0006] The present invention is directed to compounds andpharmaceutically acceptable salts thereof, compositions, and methodsuseful in modulating CCR9 chemokine activity. The compounds and saltsthereof, compositions, and methods described herein are useful intreating or preventing CCR9-mediated conditions or diseases, includingcertain inflammatory and immunoregulatory disorders and diseases.

[0007] In one embodiment, the inventive compounds are of the formula(I):

[0008] where X, Y and Z are as defined below. Salts of these compoundsare also within the scope of the invention.

[0009] In another aspect, the present invention provides compositionsuseful in modulating CCR9 chemokine activity. In one embodiment, acomposition according to the present invention comprises a compoundaccording to the invention and a pharmaceutically acceptable carrier orexcipient.

[0010] In yet another aspect, the present invention provides a method ofmodulating CCR9 function in a cell, comprising contacting the cell witha therapeutically effective amount of a compound or compositionaccording to the invention.

[0011] In still another aspect, the present invention provides a methodfor modulating CCR9 function, comprising contacting a CCR9 protein witha therapeutically effective amount of a compound or compositionaccording to the invention.

[0012] In still another aspect, the present invention provides a methodfor treating a CCR9-mediated condition or disease, comprisingadministering to a subject a safe and effective amount of a compound orcomposition according to the invention.

[0013] In addition to the compounds provided herein, the presentinvention further provides pharmaceutical compositions containing one ormore of these compounds, as well as methods for the use of thesecompounds in therapeutic methods, primarily to treat diseases associatedwith CCR9 signaling activity.

BRIEF DESCRIPTION OF THE FIGURE

[0014]FIG. 1 is a graph showing in vivo efficacy for the CCR9 antagonisttested in Example 119. Closed triangle: vehicle; Open circle: CCR9antagonist of the formula:

DETAILED DESCRIPTION OF THE INVENTION

[0015] General

[0016] The present invention is directed to compounds and salts thereof,compositions and methods useful in the modulation of chemokine receptorfunction, particularly CCR9 function. Modulation of chemokine receptoractivity, as used herein in its various forms, is intended to encompassantagonism, agonism, partial antagonism, inverse agonism and/or partialagonism of the activity associated with a particular chemokine receptor,preferably the CCR9 receptor. Accordingly, the compounds of the presentinvention are compounds which modulate at least one function orcharacteristic of mammalian CCR9, for example, a human CCR9 protein. Theability of a compound to modulate the function of CCR9, can bedemonstrated in a binding assay (e.g., ligand binding or agonistbinding), a migration assay, a signaling assay (e.g., activation of amammalian G protein, induction of rapid and transient increase in theconcentration of cytosolic free calcium), and/or cellular response assay(e.g., stimulation of chemotaxis, exocytosis or inflammatory mediatorrelease by leukocytes).

[0017] Abbreviations and Definitions

[0018] When describing the compounds, compositions, methods andprocesses of this invention, the following terms have the followingmeanings, unless otherwise indicated.

[0019] When describing the compounds, compositions, methods andprocesses of this invention, the following terms have the followingmeanings, unless otherwise indicated.

[0020] “Alkyl” by itself or as part of another substituent refers to ahydrocarbon group which may be linear, cyclic, or branched or acombination thereof having the number of carbon atoms designated (i.e.,C₁₋₈ means one to eight carbon atoms). Examples of alkyl groups includemethyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,sec-butyl, cyclohexyl, cyclopentyl, (cyclohexyl)methyl,cyclopropylmethyl and the like.

[0021] “Cycloalkyl” refers to hydrocarbon rings having the indicatednumber of ring atoms (e.g., C₃₋₆cycloalkyl) and being fully saturated orhaving no more than one double bond between ring vertices. “Cycloalkyl”is also meant to refer to bicyclic and polycyclic hydrocarbon rings suchas, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc.

[0022] “Alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane, as exemplified by—CH₂CH₂CH₂CH₂—. Typically, alkyl (or alkylene) groups having 8 or fewercarbon atoms are preferred in the present invention.

[0023] “Alkenyl” refers to an unsaturated hydrocarbon group which may belinear, cyclic or branched or a combination thereof. Alkenyl groups with2-8 carbon atoms are preferred. The alkenyl group may contain 1, 2 or 3carbon-carbon double bonds. Examples of alkenyl groups include ethenyl,n-propenyl, isopropenyl, n-but-2-enyl, n-hex-3-enyl and the like.

[0024] “Alkoxy” and “alkylthio” (or thioalkoxy) are used in theirconventional sense and refer to an alkyl groups attached to theremainder of the molecule via an oxygen atom or a sulfur atom,respectively. Examples of alkoxy and thioalkoxy include methoxy, ethoxy,isopropoxy, butoxy, cyclopentyloxy, thiomethoxy, and the like.

[0025] “Alkynyl” refers to an unsaturated hydrocarbon group which may belinear, cyclic or branched or a combination thereof. Alkynyl groups with2-8 carbon atoms are preferred. The alkynyl group may contain 1, 2 or 3carbon-carbon triple bonds. Examples of alkynyl groups include ethynyl,n-propynyl, n-but-2-ynyl, n-hex-3-ynyl and the like.

[0026] “Aryl” refers to a polyunsaturated, aromatic hydrocarbon grouphaving a single ring or multiple rings which are fused together orlinked covalently. Aryl groups with 6-10 carbon atoms are preferred.Examples of aryl groups include phenyl and naphthalene-1-yl,naphthalene-2-yl, biphenyl and the like.

[0027] “Halo” or “halogen”, by itself or as part of a substituent refersto a chlorine, bromine, iodine, or fluorine atom. Additionally,“haloalkyl” refers to a monohaloalkyl or polyhaloalkyl group, mosttypically substituted with from 1-3 halogen atoms. Examples include1-chloroethyl, 3-bromopropyl, trifluoromethyl and the like.

[0028] “Heterocyclyl” refers to a saturated or unsaturated nonaromaticgroup containing at least one heteroatom. “Heteroaryl” refers to anaromatic group containing at least one heteroatom. Each heterocyclyl andheteroaryl can be attached at any available ring carbon or heteroatom.Each heterocyclyl and heteroaryl may have one or more rings. Whenmultiple rings are present, they can be fused together or linkedcovalently. Each heterocyclyl and heteroaryl must contain at least oneheteroatom (typically 1 to 5 heteroatoms) selected from nitrogen, oxygenor sulfur. Preferably, these groups contain 0-3 nitrogen atoms, 0-1sulfur atoms and 0-1 oxygen atoms. Examples of saturated and unsaturatedheterocyclyl groups include pyrrolidine, imidazolidine, pyrazolidine,piperidine, 1,4-dioxane, morpholine, thiomorpholine, piperazine,3-pyrroline and the like. Examples of unsaturated and aromaticheterocycyl groups include pyrrole, imidazole, thiazole, oxazole, furan,thiophene, triazole, tetrazole, oxadiazole, pyrazole, isoxazole,isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, triazine,indole, benzofuran, benzothiophene, benzimidazole, benzopyrazole,benzthiazole, quinoline, isoquinoline, quinazoline, quinoxaline and thelike. Heterocyclyl and heteroaryl groups can be unsubstituted orsubstituted. For substituted groups, the substitution may be on a carbonor heteroatom. For example, when the substitution is ═O, the resultinggroup may have either a carbonyl (—C(O)—) or a N-oxide (—N(O)—).

[0029] Suitable substituents for substituted alkyl, substituted alkenyl,substituted alkynyl and substituted cycloalkyl include -halogen, —OR′,—NR′R″, —SR′, —SiR′R″ R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″,—OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —S(O)R′,—S(O)₂R′, —S(O)₂NR′R″, —NR′S(O)₂R″, —CN, oxo (═O or —O—) and —NO₂ in anumber ranging from zero to (2m′+1), where m′ is the total number ofcarbon atoms in such radical.

[0030] Suitable substituents for substituted aryl, substitutedheteroaryl and substituted heterocyclyl include-halogen, unsubstitutedor substituted alkyl, unsubstituted or substituted alkenyl,unsubstituted or substituted alkynyl, unsubstituted or substitutedcycloalkyl, —OR′, oxo (═O or —O), —OC(O)R′, —NR′R″, —SR′, —R′, —CN,—NO₂, —CO₂R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O)₂R′,—NR′—C(O)NR″R′″, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —S(O)R′,—S(O)₂R′, —S(O)₂NR′R″, —NR′S(O)₂R″ and —N₃ in a number ranging from zeroto the total number of open valences on the aromatic ring system.

[0031] As used above, R′, R″ and R′″ each independently refer to avariety of groups including hydrogen, halogen, unsubstituted orsubstituted C₁₋₈ alkyl, unsubstituted or substituted C₃₋₆ cycloalkyl,unsubstituted or substituted C₂₋₈ alkenyl, unsubstituted or substitutedC₂₋₈ alkynyl, unsubstituted or substituted aryl, unsubstituted orsubstituted heteroaryl, unsubstituted or substituted heterocyclyl.Preferably, R′, R″ and R′″ independently refer to a variety of groupsselected from the group consisting of hydrogen, unsubstituted C₁₋₈alkyl, unsubstituted heteroalkyl, unsubstituted aryl, aryl substitutedwith 1-3 halogens, unsubstituted C₁₋₈alkyl, unsubstituted C₁₋₈alkoxy,unsubstituted C₁₋₈ thioalkoxy groups, or unsubstituted aryl-C₁₋₄ alkylgroups. When R′ and R″ are attached to the same nitrogen atom, they canbe combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or7-membered ring (for example, —NR′R″ includes 1-pyrrolidinyl and4-morpholinyl).

[0032] Alternatively, two of the substituents on adjacent atoms of thearyl, heteroaryl or heterocycyl ring may optionally be replaced with asubstituent of the formula -T-C(O)—(CH₂)_(q)—U—, wherein T and U areindependently —NR′—, —O—, —CH₂— or a single bond, and q is an integer offrom 0 to 2. Alternatively, two of the substituents on adjacent atoms ofthe aryl or heteroaryl ring may optionally be replaced with asubstituent of the formula -A-(CH₂)_(r)—B—, wherein A and B areindependently —CH₂—, —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or asingle bond, and r is an integer of from 1 to 3. One of the single bondsof the new ring so formed may optionally be replaced with a double bond.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula —(CH₂)_(s)—X—(CH₂)_(t)—, where s and t are independentlyintegers of from 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituent R′ in —NR′— and —S(O)₂NR′— is selected fromhydrogen or unsubstituted C₁₋₆ alkyl.

[0033] “Heteroatom” is meant to include oxygen (O), nitrogen (N), sulfur(S) and silicon (Si).

[0034] “Pharmaceutically acceptable” carrier, diluent, or excipient is acarrier, diluent, or excipient compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

[0035] “Pharmaceutically-acceptable salt” refers to a salt which isacceptable for administration to a patient, such as a mammal (e.g.,salts having acceptable mammalian safety for a given dosage regime).Such salts can be derived from pharmaceutically-acceptable inorganic ororganic bases and from pharmaceutically-acceptable inorganic or organicacids, depending on the particular substituents found on the compoundsdescribed herein. When compounds of the present invention containrelatively acidic functionalities, base addition salts can be obtainedby contacting the neutral form of such compounds with a sufficientamount of the desired base, either neat or in a suitable inert solvent.Salts derived from pharmaceutically-acceptable inorganic bases includealuminum, ammonium, calcium, copper, ferric, ferrous, lithium,magnesium, manganic, manganous, potassium, sodium, zinc and the like.Salts derived from pharmaceutically-acceptable organic bases includesalts of primary, secondary, tertiary and quaternary amines, includingsubstituted amines, cyclic amines, naturally-occurring amines and thelike, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine, tromethamineand the like. When compounds of the present invention contain relativelybasic functionalities, acid addition salts can be obtained by contactingthe neutral form of such compounds with a sufficient amount of thedesired acid, either neat or in a suitable inert solvent. Salts derivedfrom pharmaceutically-acceptable acids include acetic, ascorbic,benzenesulfonic, benzoic, camphosulfonic, citric, ethanesulfonic,fumaric, gluconic, glucoronic, glutamic, hippuric, hydrobromic,hydrochloric, isethionic, lactic, lactobionic, maleic, malic, mandelic,methanesulfonic, mucic, naphthalenesulfonic, nicotinic, nitric, pamoic,pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonicand the like.

[0036] Also included are salts of amino acids such as arginate and thelike, and salts of organic acids like glucuronic or galactunbric acidsand the like (see, for example, Berge, S. M., et al, “PharmaceuticalSalts”, J. Pharmaceutical Science, 1977, 66:1-19). Certain specificcompounds of the present invention contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts.

[0037] The neutral forms of the compounds may be regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents, but otherwise the salts are equivalentto the parent form of the compound for the purposes of the presentinvention.

[0038] “Salt thereof” refers to a compound formed when the hydrogen ofan acid is replaced by a cation, such as a metal cation or an organiccation and the like. Preferably, the salt is apharmaceutically-acceptable salt, although this is not required forsalts of intermediate compounds which are not intended foradministration to a patient.

[0039] In addition to salt forms, the present invention providescompounds which are in a prodrug form. Prodrugs of the compoundsdescribed herein are those compounds that readily undergo chemicalchanges under physiological conditions to provide the compounds of thepresent invention. Additionally, prodrugs can be converted to thecompounds of the present invention by chemical or biochemical methods inan ex vivo environment. For example, prodrugs can be slowly converted tothe compounds of the present invention when placed in a transdermalpatch reservoir with a suitable enzyme or chemical reagent.

[0040] “Therapeutically effective amount” refers to an amount sufficientto effect treatment when administered to a patient in need of treatment.

[0041] “Treating” or “treatment” as used herein refers to the treatingor treatment of a disease or medical condition (such as a bacterialinfection) in a patient, such as a mammal (particularly a human or acompanion animal) which includes:

[0042] ameliorating the disease or medical condition, i.e., eliminatingor causing regression of the disease or medical condition in a patient;

[0043] suppressing the disease or medical condition, i.e., slowing orarresting the development of the disease or medical condition in apatient; or

[0044] alleviating the symptoms of the disease or medical condition in apatient.

[0045] Certain compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, both solvated forms and unsolvated forms are intended to beencompassed within the scope of the present invention. Certain compoundsof the present invention may exist in multiple crystalline or amorphousforms (i.e., as polymorphs). In general, all physical forms areequivalent for the uses contemplated by the present invention and areintended to be within the scope of the present invention.

[0046] Certain compounds of the present invention possess asymmetriccarbon atoms (optical centers) or double bonds; the racemates,diastereomers, geometric isomers and individual isomers (e.g., separateenantiomers) are all intended to be encompassed within the scope of thepresent invention. The compounds of the present invention may alsocontain unnatural proportions of atomic isotopes at one or more of theatoms that constitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areintended to be encompassed within the scope of the present invention.

[0047] Compounds that Modulate CCR9 Activity

[0048] The present invention provides compounds that modulate CCR9activity. Specifically, the invention provides compounds havinganti-inflammatory or immunoregulatory activity. The compounds of theinvention are thought to interfere with inappropriate T-cell traffickingby specifically modulating or inhibiting a chemokine receptor function.Chemokine receptors are integral membrane proteins which interact withan extracellular ligand, such as a chemokine, and mediate a cellularresponse to the ligand, e.g., chemotaxis, increased intracellularcalcium ion concentration, etc. Therefore, modulation of a chemokinereceptor function, e.g., interference with a chemokine receptor ligandinteraction, will modulate a chemokine receptor mediated response, andtreat or prevent a chemokine receptor mediated condition or disease.Modulation of a chemokine receptor function includes both inducement andinhibition of the function. The type of modulation accomplished willdepend on the characteristics of the compound, i.e., antagonist or full,partial or inverse agonist.

[0049] Without intending to be bound by any particular theory, it isbelieved that the compounds provided herein interfere with theinteraction between a chemokine receptor and one or more cognateligands. In particular, it is believed that the compounds interfere withthe interaction between CCR9 and a CCR9 ligand, such as TECK. Compoundscontemplated by the invention include, but are not limited to, theexemplary compounds provided herein and salts thereof.

[0050] For example, compounds of this invention act as potent CCR9antagonists, and this antagonistic activity has been further confirmedin animal testing for inflammation, one of the hallmark disease statesfor CCR9. Accordingly, the compounds provided herein are useful inpharmaceutical compositions, methods for the treatment of CCR9-mediateddiseases, and as controls in assays for the identification ofcompetitive CCR9 antagonists.

[0051] CCR9 Antagonists as Treatments of Cancer

[0052] In additional to inflammatory diseases, cancers that are causedby uncontrolled proliferation of T cells may be treated with a CCR9antagonist. Certain types of cancer are caused by T cells expressingchemokine receptor CCR9. For example, thymoma and thymic carcinoma arediseases in which cancer cells are found in the tissues of the thymus,an organ where lymphocyte development occurs. T cells in the thymus,called thymocytes, are known to express functional CCR9; its ligand ishighly expressed in the thymus. Another example is the acute lymphocyticleukemia (ALL), also called acute lymphoblastic leukemia and acute, is acommon leukemia, which can occur in children as well as adults. Recentstudies have shown that T cells in patients with ALL selectively expresshigh level of CCR9 (Qiuping Z et al., Cancer Res. 2003,1;63(19):6469-77)

[0053] Chemokine receptors have been implicated in cancer. Although theexact mechanisms of chemokine receptors' involvements have yet to befull understood, such receptors are known to promote the growth ofcancer cells (proliferation), facilitate the spread of cancer cells(metastasis) or help them resist program cell death (apoptosis). Forexample, CCR9 in a cancer T cell line MOLT-4 provides the cells with asurvival signal, allowing them to resist apoptosis (Youn B S, et al.,Apoptosis. 2002 June;7(3):271-6). In the cases of thymoma, thymiccarcinoma and acute lymphocytic leukemia, it is likely that CCR9 plays akey in the survival and proliferation these cells. Thus, blocking thesignaling of CCR9 should help prevent their expansion and metastasis.

[0054] Compounds of the Invention

[0055] The compounds provided herein have the general formula (I):

[0056] X Substituents

[0057] X represents from 1 to 4 substituents independently selected fromthe group consisting of halogen, —CN, —NO₂, —OH, —OR¹, —C(O)R¹, —CO₂R¹,—O(CO)R¹, —C(O)NR¹R², —OC(O)NR¹R², —SR¹, —SOR¹, —SO₂R¹, —SO₂NR¹R²,—NR¹R², —NR¹C(O)R², —NR¹C(O)₂R², —NR¹SO₂R², —NR¹(CO)NR¹R², unsubstitutedor substituted C₁₋₈ alkyl, unsubstituted or substituted C₂₋₈ alkenyl,unsubstituted or substituted C₂₋₈ alkynyl, unsubstituted or substitutedC₃₋₈ cycloalkyl, unsubstituted or substituted C₆₋₁₀ aryl, unsubstitutedor substituted 5- to 10-membered heteroaryl, and unsubstituted orsubstituted 3- to 10-membered heterocyclyl.

[0058] When X is substituted C₁₋₈alkyl, substituted C₃₋₈ cycloalkyl,substituted C₂₋₈ alkenyl, or substituted C₂₋₈ alkynyl, it may have from1-5 substituents independently selected from the group consisting ofhalogen, —OH, —CN, —NO₂, ═O, —OC(O)R¹, —OR¹, —C(O)R¹, —CONR¹R²,—OC(O)NR¹R², —NR²C(O)R¹, —NR¹C(O)NR²R³, —CO₂R¹, —NR¹R², —NR²CO₂R¹, —SR¹,—SOR¹, —SO₂R¹, —SO₂NR¹R², —NR¹SO₂R², unsubstituted or substituted aryl,unsubstituted or substituted heteroaryl, and unsubstituted orsubstituted heterocyclyl.

[0059] When X is substituted C₆₋₁₀ aryl, substituted 5- to 10-memberedheteroaryl, or substituted 3- to 10-membered heterocyclyl, it may havefrom 1-4 substituents independently selected from the group consistingof halogen, unsubstituted or substituted C₁₋₈ alkyl, unsubstituted orsubstituted C₁₋₈ haloalkyl, —CN, —NO₂, —OH, —OR¹, ═O, —OC(O)R¹, —CO₂R¹,—C(O)R¹, —CONR¹R², —OC(O)NR¹, R², —NR²C(O)R¹, —NR¹C(O)NR²R³, —NR¹R²,—NR²CO₂R¹, —SR¹, —SOR¹, —SO₂R¹, —SO₂NR¹R², and —NR¹SO₂R². Suitablesubstituted C₁₋₈ alkyl include those defined above in paragraph [0051].

[0060] R¹, R² and R³ are each independently selected from the groupconsisting of hydrogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl,aryl-C₁₋₄ alkyl, aryl-C₁₋₄ alkyl, and aryloxy-C₁₋₄ alkyl. Each can beunsubstituted or substituted with from 1-3 substituents independentlyselected from the group consisting of halogen, —OH, —OR′, —OCOHNR′,—OCONR′₂, —SH, —SR′, —SO₂NH₂, —CONH₂, —NHC(O)NH₂, NR′C(O)NH₂, —CO₂H,—CN, —NO₂, —NH₂, —NHR′ and —NR′₂, —S(O)R′, —S(O)₂R′, —CO₂R′, —CONR′₂,—CONHR′, —C(O)R′, —NR′COR′, —NHCOR′, —NR′CO₂R′, —NHCO₂R′, —CO₂R′,—NR′C(O)NR′₂, —NHC(O)NR′₂, —NR′C(O)NHR′, —NHC(O)NHR′, —NR′SO₂R′,—NHSO₂R′, —SO₂NR′₂, and —SO₂NHR′. Alternatively, two of R¹, R² and R³together with the atom(s) to which they are attached, may form a 5-, 6-or 7-membered ring.

[0061] Y Substituents

[0062] Y represents from 1 to 3 substituents, each independentlyselected from the group consisting of halogen, —CN, —NO₂, —OH, —OR⁴,—C(O)R⁴, —CO₂R⁴, —SR⁴, —SOR⁴, —SO₂R⁴, and unsubstituted or substitutedC₁₋₄ alkyl.

[0063] When Y is a substituted C₁₋₄ alkyl, it may have from 1 to 3substituents independently selected from the group consisting ofhalogen, —OH, —OR⁴, —CN, —NO₂, ═O, —OC(O)R⁴, —CO₂R⁴, —C(O)R⁴, —CONR⁴R⁵,—OC(O)NR⁴R⁵, —NR⁴C(O)R⁵, —NR⁴C(O)NR⁵R⁶, —NR⁴R⁵, —NR⁴CO₂R⁵, —SR⁴, —SOR⁴,—SO₂R⁴, —SO₂NR⁴R⁵, and —NR⁴SO₂R⁵.

[0064] R⁴, R⁵ and R⁶ are each independently selected from the groupconsisting of hydrogen, unsubstituted or substituted C₁₋₆ haloalkyl,unsubstituted or substituted C₁₋₆ alkyl, unsubstituted or substitutedC₃₋₆ cycloalkyl, unsubstituted or substituted C₂₋₆alkenyl, andunsubstituted or substituted C₂₋₆ alkynyl. Each can be unsubstituted orsubstituted with from 1 to 3 substituents independently selected fromthe group consisting of —OH, —OR′, —SH, —SR′, —CN, —NO₂, —NH₂, —NHR′,—NR′₂, —S(O)R′, —S(O)₂R′, —CO₂R′, —CONHR′, —CONR′₂, and —C(O)R′.Additionally, two of R⁴, R⁵ and R⁶ together with the atom(s) to whichthey are attached, may form a 5-, 6- or 7-membered ring.

[0065] Linkers

[0066] L is —C(O)—, —S—, —SO— or —S(O)₂—.

[0067] Z Substituents

[0068] Z represents either unsubstituted or substituted monocyclic orbicyclic C₅₋₁₀ heteroaryl or unsubstituted or substituted monocyclic orbicyclic C₃₋₁₀ heterocyclyl.

[0069] When Z is a substituted heteroaryl or substituted heterocyclyl,it may have from 1 to 5 substituents independently selected from thegroup consisting of halogen, unsubstituted or substituted C₁₋₈ alkyl,unsubstituted or substituted C₁₋₈ cycloalkyl, unsubstituted orsubstituted C₂₋₈ alkenyl, unsubstituted or substituted C₂₋₈ alkynyl,unsubstituted or substituted C₁₋₈ alkoxy, ═O, —CN, —NO₂, —OH, —OR⁷,—OC(O)R⁷—CO₂R⁷, —C(O)R⁷, —CONR⁷R⁸, —OC(O)NR⁷R⁸, —NR⁷C(O)R⁸,—NR⁷C(O)NR⁸R⁹, —NR⁷R⁸, —NR⁷CO₂R⁸, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁷R⁸,—NR⁷SO₂R⁸, unsubstituted or substituted C₆₋₁₀ aryl, unsubstituted orsubstituted heteroaryl and unsubstituted or substituted heterocyclyl.

[0070] Suitable substituted C₁₋₈ alkyl, C₃₋₈ cycloalkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl and C₁₋₈ alkoxy substituents on Z may have from 1 to 5substituents independently selected from the group consisting ofhalogen, —OH, —OR⁷, —CN, —NO₂, ═O, —CN, —NO₂, —OC(O)R⁷, —CO₂R⁷,—C(O)R⁷—CONR⁷R⁸, —OC(O)NR⁷R⁸, —NR⁷C(O)R⁸, —NR⁷C(O)NR⁸R⁹, —NR⁷R⁸,—NR⁷CO₂R⁸, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁷R⁸, —NR⁷SO₂R⁸, unsubstituted orsubstituted phenyl, unsubstituted or substituted 5- or 6-memberedheteroaryl, or unsubstituted or substituted 3- to 6-memberedheterocyclyl.

[0071] Suitable substituted aryl, heteroaryl and heterocyclylsubstituents on Z may have from 1 to 5 substituents independentlyselected from the group consisting of halogen, —OH, —OR⁷, —CN, —NO₂, ═O,—CN, —NO₂, —OC(O)R⁷, —OC(O)R⁷, —CO₂R⁷, —C(O)R⁷, —CONR⁷R⁸, —OC(O)NR⁷R⁸,—NR⁷C(O)R⁸, —NR⁷C(O)NR⁸R⁹, —NR⁷R⁸, —NR⁷CO₂R⁸, —SR⁷, —SOR⁷, —SO₂R⁷,—SO₂NR⁷R⁸, —NR⁷SO₂R⁸ and unsubstituted or substituted C₃₋₆ heterocyclyl.

[0072] R⁷, R⁸ and R⁹ are each independently hydrogen, unsubstituted orsubstituted C₁₋₆ haloalkyl, unsubstituted or substituted C₁₋₆ alkyl,unsubstituted or substituted C₃₋₆ cycloalkyl, unsubstituted orsubstituted C₂₋₆ alkenyl, unsubstituted or substituted C₂₋₆ alkynyl,unsubstituted or substituted phenyl or unsubstituted or substitutedheteroaryl, unsubstituted or substituted aryl-C₁₋₄ alkyl, andunsubstituted or substituted aryloxy-C₁₋₄ alkyl. Each can be substitutedwith from 1 to 3 substituents independently selected from the groupconsisting of halogen, —OH, —OR′, —OCONHR′, —OCONR′₂, —SH, —SR′,—SO₂NH₂, —CONH₂, —NHC(O)NH₂, NR′C(O)NH₂, —CO₂H, —CN, —NO₂, —NH₂, —NHR′and —NR′₂, —S(O)R′, —S(O)₂R′, —CO₂R′, —CONR′₂, —CONHR′, —C(O)R′,—NR′COR′, —NHCOR′, —NR′CO₂R′, —NHCO₂R′, —CO₂R′, —NR′C(O)NR′₂,—NHC(O)NR′₂, —NR′C(O)NHR′, —NHC(O)NHR′, —NR′SO₂R′, —NHSO₂R′, —SO₂NR′₂,and —SO₂NHR′. R′ is defined above. It is preferably, unsubstituted orsubstituted C₁₋₆ alkyl. Alternatively, two of R⁷, R⁸ and R⁹ togetherwith the atom(s) to which they are attached, may form a 5-, 6- or7-membered ring.

[0073] Known Compounds

[0074] Compounds of the formula (I) where X is methyl when Z is2-thiophene, 2-(3-hydroxy-1H-indole) or 3-(1-methylpyridinium) areknown, but not as CCR9 antagonists.

[0075] Preferred X Substituents

[0076] X preferably represents from 1 to 3 substituents independentlyselected from the group consisting of halogen, —CN, —NO₂, —OH, —OR¹,—C(O)R¹, —CO₂R¹, —O(CO)R¹, —OC(O)NR¹R², —SR¹, —SOR¹, —SO₂R¹, —NR¹R²,—NR¹C(O)R², —NR¹C(O)₂R², —NR¹(CO)NR¹R², unsubstituted or substitutedC₁₋₈ alkyl, unsubstituted or substituted C₂₋₈ alkenyl, unsubstituted orsubstituted C₂₋₈ alkynyl, unsubstituted or substituted C₃₋₈ cycloalkyl,unsubstituted or substituted C₆₋₁₀ aryl, unsubstituted or substituted 5-or 6-membered heteroaryl, or unsubstituted or substituted 4- to7-membered heterocyclyl.

[0077] X more preferably represents 1 or 2 substituents independentlyselected from the group consisting of —NO₂, —OR¹, —C(O)R¹, —SO₂R¹,—NR¹R², unsubstituted or substituted C₁₋₈ alkyl, unsubstituted orsubstituted phenyl, unsubstituted or substituted 5- or 6-memberedheteroaryl, or unsubstituted or substituted 5- or 6-memberedheterocyclyl. More preferably, at least one X substituent is situatedpara to the sulfonamido bond as defined in formula (I).

[0078] When X is substituted C₁₋₈ alkyl or substituted C₃₋₈ cycloalkyl,it preferably has from 1 to 3 substituents independently selected fromthe group consisting of halogen, —OH, —CN, ═O, —OC(O)R¹, —OR¹, —C(O)R¹,—CONR¹R², —NR²C(O)R¹, —CO₂R¹, —NR¹R², —SR¹, —SOR¹, —SO₂R¹, —NR¹SO₂R²,unsubstituted or substituted aryl, and unsubstituted or substitutedheteroaryl. When X is a substituted C₁₋₈ alkyl, it more preferably hasfrom 1 to 3 substituents independently selected from the groupconsisting of halogen, —OH, —CN, ═O, —OC(O)R¹, —OR¹, —C(O)R¹, —CONR¹R²,—NR²C(O)R¹, —CO₂R¹, —NR¹R², —SO₂R¹, unsubstituted or substituted aryl,and unsubstituted or substituted heteroaryl.

[0079] When X is substituted C₆₋₁₀ aryl or substituted heteroaryl, itpreferably has from 1 to 3 substituents independently selected from thegroup consisting of halogen, —CN, —OH, —OR¹, ═O, —OC(O)R¹, —CO₂R¹,—C(O)R¹, —CONR¹R², —NR²C(O)R¹, —NR¹R², —SR¹, —SOR¹, —SO₂R¹, —NR¹SO₂R²,unsubstituted or substituted C₁₋₈ alkyl, and C₁₋₈ unsubstituted orsubstituted haloalkyl. When X is a substituted phenyl or substituted 5-or 6-membered heteroaryl, it is more preferably has from 1 to 3substituents independently selected from the group consisting ofhalogen, —OH, —OR¹, —C(O)R¹, —CONR¹R², —NR²C(O)R¹, —NR¹R², —SO₂R¹,unsubstituted or substituted C₁₋₈ alkyl, and unsubstituted orsubstituted C₁₋₈ haloalkyl.

[0080] When X is a substituted 4- to 7-membered heterocyclyl, itpreferably has from 1 to 3 substituents independently selected from thegroup consisting of unsubstituted or substituted C₁₋₈ alkyl, C₁₋₈haloalkyl, —OR¹, —OH, —OC(O)R¹, —CO₂R¹, —C(O)R¹, —CONR¹R², —NR¹R²,—SO₂R¹, and —NR¹SO₂R². When X is a 5- or 6-membered heterocyclyl, itmore preferably has 1 to 2 substituents independently selected from thegroup consisting of unsubstituted or substituted C₁₋₈ alkyl,unsubstituted or substituted C₁₋₈ haloalkyl, unsubstituted orsubstituted C₁₋₈ haloalkyl, —OR¹, —OH, —C(O)R¹, —CONR¹R², —NR¹R², and—SO₂R¹.

[0081] Preferred Y Substituents

[0082] Y preferably represents from 1 to 3 substituents independentlyselected from the group consisting of halogen, —CN, —NO₂, —OR⁴, —C(O)R⁴,—SR⁴, —CF₃, —SOR⁴, and —SO₂R⁴. Y more preferably represents from 1 to 3substituents independently selected from the group consisting ofhalogen, —CN, —NO₂, —CF₃, and —SO₂R⁴. Y most preferably represents 1 or2 substituents where at least halogen is present and optionally anothersubstituent selected from the group consisting of —CN, —NO₂, —OH, —OR⁴,—C(O)R⁴, —CO₂R⁴, —SR⁴, —SOR⁴, —SO₂R⁴ and unsubstituted or substitutedC₁₋₄ alkyl. Most preferably, at least one Y substituent is located parato the sulfonamide bond as defined in formula (I), and one Y substituentis halogen.

[0083] When Y is substituted alkyl, it preferably has from 1 to 3substituents independently selected from the group consisting ofhalogen, —OH, —OR⁴, —CN, —NO₂, ═O, —OC(O)R⁴, —CO₂R⁴, —C(O)R⁴, —CONR⁴R⁵,—NR⁴C(O)R⁵—NR⁴R⁵, —NR⁴, —SR⁴, —SOR⁴—SO₂R⁴, and —NR⁴SO₂R⁵.

[0084] Preferred Linkers

[0085] L is preferably —C(O)—.

[0086] Preferred Z Substituents

[0087] Z preferably represents an unsubstituted or substituted 5- or6-membered heteroaryl.

[0088] When Z is a substituted 5- or 6-membered heteroaryl, itpreferably has from 1 to 3 substituents independently selected from thegroup consisting of halogen, unsubstituted or substituted C₁₋₈ alkyl,unsubstituted or substituted C₃₋₈ cycloalkyl, unsubstituted orsubstituted C₂₋₈ alkenyl, unsubstituted or substituted C₂₋₈ alkynyl,unsubstituted or substituted C₁₋₈ alkoxy, ═O, —CN, —NO₂, —OH, —OR⁷,—OC(O)R⁷, —CO₂R⁷, —C(O)R⁷, —CONR⁷R⁸, —NR⁷C(O)R⁸, —NR⁷R⁸, —SR⁷, —SOR⁷,—SO₂R⁷, —SO₂NR⁷R⁸, —NR⁷SO₂R⁸, unsubstituted or substituted phenyl,unsubstituted or substituted 5- or 6-membered heteroaryl, andunsubstituted or substituted 3- to 7-membered heterocyclyl. If present,one substituent is preferably located ortho to one of the heteroatoms inthe ring or is directly connected to a ring heteroatom.

[0089] Z more preferably represents unsubstituted or substituted6-membered heteroaryl with carbon and up to 3 nitrogen atoms and withfrom 1 to 3 substituents independently selected from the groupconsisting of halogen, C₁₋₈ alkyl, C₃₋₈ cycloalkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, C₁₋₈alkoxy, ═O, —CN, —NO₂, —OH, —OR⁷, —OC(O)R⁷, —CO₂R⁷,—C(O)R⁷, —CONR⁷R⁸, —NR⁷C(O)R⁸, —NR⁷R⁸, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁷R⁸,—NR⁷SO₂R⁸, unsubstituted or substituted phenyl, unsubstituted orsubstituted 5- and 6-membered heteroaryl, and unsubstituted orsubstituted 3- to 6-membered heterocyclyl. In this embodiment, Z can beany unsubstituted or substituted chemically allowed regioisomers ofpyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and the like and theirrespective N-oxides. In preferred embodiments, Z is pyridinyl with from0 to 3 substituents; pyrimidinyl with from 0 to 3 substituents;pyrazinyl with from 0 to 3 substituents; or pyridazinyl with from 0 to 3substituents (especially, where one ring nitrogen has a ═O substituent).

[0090] Z most preferably represents unsubstituted or substituted6-membered heteroaryl with carbon and 1 to 2 nitrogen atoms and with 1or 2 substituents independently selected from the group consisting ofhalogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, ═O, —CN, —NO₂, —OH, —OR⁷, —C(O)R⁷,—CONR⁷R⁸, —NR⁷C(O)R⁸, —NR⁷R⁸, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁷R⁸, —NR⁷SO₂R⁸,5- or 6-membered heteroaryl and a 3- to 7-membered heterocyclyl. In thisembodiment, Z can be any chemically allowed regioisomers of pyridyl,pyrimidinyl, pyridazinyl, pyrazinyl and the like, and their respectiveN-oxides.

[0091] When the substituent on Z is substituted C₁₋₈ alkyl, substitutedC₃₋₈ cycloalkyl, substituted C₂₋₈ alkenyl, substituted C₂₋₈ alkynyl orsubstituted C₁₋₈ alkoxy groups, it preferably has from 1 to 3substituents independently selected from the group consisting ofhalogen, —OH, —OR⁷, ═O, —CO₂R⁷, —C(O)R⁷, —CONR⁷R⁸, —NR⁷C(O)R⁸, —NR⁷R⁸,—SR⁷, —SOR⁷, —SO₂R⁷, —NR⁷SO₂R⁸, unsubstituted or substituted phenyl,unsubstituted or substituted 5- or 6-membered heteroaryl, andunsubstituted or substituted 3- to 6-membered heterocyclyl. Morepreferably, it has from 1 to 3 substituents independently selected fromthe group consisting of halogen, —OH, —OR⁷, ═O, —C(O)R⁷, —CO₂R⁷,—CONR⁷R⁸, —NR⁷C(O)R⁸, —NR⁷R⁸, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁷R⁸, —NR⁷SO₂R⁸,and 3- to 6-membered heterocyclyl.

[0092] When the substituent on Z is substituted phenyl or substitutedheteroaryl, it preferably has from 1 to 3 substituents independentlyselected from the group consisting of halogen, —OH, —OR⁷, —CN, —NO₂, ═O,—CN, —NO₂, —OC(O)R⁷, —CO₂R⁷, —C(O)R⁷, —CONR⁷R⁸, —NR⁷C(O)R⁸, —NR⁷R⁸,—SR⁷, —SOR⁷, —SO₂R⁷, —NR⁷SO₂R⁸, unsubstituted or substituted C₁₋₈ alkyl,unsubstituted or substituted C₁₋₈ haloalkyl, unsubstituted orsubstituted C₃₋₈ cycloalkyl, and 3- to 6-membered heterocyclyl.

[0093] When the substituent on Z is substituted heterocyclyl, itpreferably has from 1 to 2 substituents independently selected from thegroup consisting of unsubstituted or substituted C₁₋₈ alkyl, C₁₋₈haloalkyl, —OR⁷, —OH, —C(O)R⁷, —CONR⁷R⁸, —NR⁷R⁸, and —SO₂R⁷.

[0094] Preferred Compounds

[0095] In several preferred embodiments, the compounds are representedby the following formulae:

[0096] In each of the above formulae, X′ and X″ are each independentlyselected from the group consisting of hydrogen, halogen, —CN, —NO₂, —OH,—OR¹, —C(O)R¹, —CO₂R¹, —O(CO)R¹, —C(O)NR¹R², —OC(O)NR¹R², —SR¹, —SOR¹,—SO₂R¹, —SO₂NR¹R², —NR¹R², —NR¹C(O)R², —NR¹C(O)₂R², —NR¹SO₂R²,—NR¹(CO)NR¹R², unsubstituted or substituted C₁₋₈ alkyl, unsubstituted orsubstituted C₁₋₈ haloalkyl, unsubstituted or substituted C₂₋₈ alkenyl,unsubstituted or substituted C₂₋₈ alkynyl, unsubstituted or substitutedC₃₋₈ cycloalkyl, unsubstituted or substituted C₆₋₁₀ aryl, unsubstitutedor substituted 5- to 10-membered heteroaryl, and unsubstituted orsubstituted 3- to 10-membered heterocyclyl, with the proviso that X′ andX″ cannot both be hydrogen simultaneously.

[0097] In one preferred embodiment, X′ and X″ are each independentlyselected from the group consisting of hydrogen, —NO₂, —OR¹, —C(O)R¹,—SO₂R′, —NR¹R², unsubstituted or substituted C₁₋₈ alkyl, unsubstitutedor substituted C₁₋₈ haloalkyl, unsubstituted or substituted C₃₋₈cycloalkyl, unsubstituted or substituted C₂₋₈ alkenyl, unsubstituted orsubstituted phenyl, unsubstituted or substituted 5- or 6-memberedheteroaryl, unsubstituted or substituted 5- or 6-membered heterocyclyl,with the proviso that X′ and X″ cannot both be hydrogen simultaneously.

[0098] In another preferred embodiment, X′ and X″ are each independentlyselected from the group consisting of hydrogen, —CF₃, —CH═CH₂, isoamyl,phenylacetylene, t-butyl, ethyl (Et), i-propyl (^(i)Pr), —C(CH₃)₂CH₂CH₃,hydroxybutyl, —C(CH₃)₂CH₂CH₂OH, —CH₂CH₂CO₂Me, —OCF₃, —OMe, —O—¹Pr,—C(O)Me, —SO₂Me, phenyl (Ph), —OEt, pyrazole, oxazole, and morpholinyl,with the proviso that X′ and X″ cannot both be hydrogen simultaneously.

[0099] In each of the above formulae, Y′ and Y″ are each independentlyselected from the group consisting of hydrogen, halogen, —CN, —NO₂, —OH,—OR⁴, —C(O)R⁴, —CO₂R⁴, —SR⁴, —SOR⁴, —SO₂R⁴, unsubstituted or substitutedC₁₋₄ alkyl, and unsubstituted or substituted C₁₋₄ haloalkyl, with theproviso that Y′ and Y″ cannot both be hydrogen simultaneously.

[0100] In one preferred embodiment, Y′ and Y″ are each independentlyhydrogen or halogen, with the proviso that one or both are halogen. Morepreferably, Y′ is hydrogen and Y″ is chloro; Y′ and Y″ are both fluoro;Y′ is hydrogen and Y″ is fluoro; or Y′ is hydrogen and Y″ is bromo. Mostpreferably, one halogen atom is para to the sulfonamide bond in formula(I).

[0101] In each of the above formulae, Z′ and Z″ are each independentlyselected from the group consisting of hydrogen, halogen, unsubstitutedor substituted C₁₋₈ alkyl, unsubstituted or substituted C₃₋₈ cycloalkyl,unsubstituted or substituted C₂₋₈ alkenyl, unsubstituted or substitutedC₂₋₈ alkynyl, unsubstituted or substituted C₁₋₈ alkoxy, ═O, —CN, —NO₂,—OH, —OR⁷, —OC(O)R⁷, —CO₂R⁷, —C(O)R⁷, —CONR⁷R⁸, —OC(O)NR⁷R⁸, —NR⁷C(O)R⁸,—NR⁷C(O)NR⁸R⁹, —NR⁷R⁸, —NR⁷CO₂R⁸, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁷R⁸,—NR⁷SO₂R⁸, unsubstituted or substituted C₆₋₁₀ aryl, unsubstituted orsubstituted 5- or 6-membered heteroaryl and unsubstituted or substituted3- to 7-membered heterocyclyl.

[0102] In one preferred embodiment, Z′ and Z″ are each independentlyselected from the group consisting of hydrogen, halogen, unsubstitutedor substituted C₁₋₈ alkyl, unsubstituted or substituted C₃₋₈ cycloalkyl,—CN, —OH, —OR⁷, —C(O)R⁷, —CO₂R⁷, —OC(O)R⁷, —CONR⁷R⁸, —NR⁷R⁸—NR⁷CO₂R⁸,—SR⁷, —SOR⁷, —SO₂R⁷, —NR⁷SO₂R⁸, unsubstituted or substituted C₆₋₁₀ aryl,and unsubstituted or substituted 5- or 6-membered heteroaryl.

[0103] In a more preferred embodiment, Z′ and Z″ are each independentlyhydrogen, halogen, —CN, —OR⁷, —NR⁷R⁸, —SR⁷ (e.g., thiomethyl), —SOR⁷,and —SO₂R⁷ (e.g., methylsulfonyl), unsubstituted or substituted C₁₋₆alkoxyl (e.g., methoxy), unsubstituted or substituted C₁₋₆ alkyl (e.g.,methyl), unsubstituted or substituted phenyl, or unsubstituted orsubstituted 5- or 6-membered heterocyclyl.

[0104] Compositions that Modulate CCR9 Activity

[0105] In another aspect, the present invention provides compositionsthat modulate CCR9 activity. Generally, the compositions for modulatingchemokine receptor activity in humans and animals will comprise apharmaceutically acceptable excipient or diluent and a compound havingthe formula provided above as formula (I).

[0106] The term “composition” as used herein is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

[0107] The pharmaceutical compositions for the administration of thecompounds of this invention may conveniently be presented in unit dosageform and may be prepared by any of the methods well known in the art ofpharmacy. All methods include the step of bringing the active ingredientinto association with the carrier which constitutes one or moreaccessory ingredients. In general, the pharmaceutical compositions areprepared by uniformly and intimately bringing the active ingredient intoassociation with a liquid carrier or a finely divided solid carrier orboth, and then, if necessary, shaping the product into the desiredformulation. In the pharmaceutical composition the active objectcompound is included in an amount sufficient to produce the desiredeffect upon the process or condition of diseases.

[0108] The pharmaceutical compositions containing the active ingredientmay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsions and self emulsifications as described in U.S. PatentApplication 20020012680, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions. Such compositions may contain one or more agents selectedfrom sweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets contain the active ingredient in admixture withother non-toxic pharmaceutically acceptable excipients which aresuitable for the manufacture of tablets. These excipients may be, forexample, inert diluents such as cellulose, silicon dioxide, aluminumoxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example PVP, cellulose, PEG, starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coatedenterically or otherwise by known techniques to delay disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. For example, a time delay material such asglyceryl monostearate or glyceryl distearate may be employed. They mayalso be coated by the techniques described in the U.S. Pat. Nos.4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tabletsfor control release.

[0109] Formulations for oral use may also be presented as hard gelatincapsules wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin, orolive oil. Additionally, emulsions can be prepared with a non-watermiscible ingredient such as oils and stabilized with surfactants such asmono-diglycerides, PEG esters and the like.

[0110] Aqueous suspensions contain the active materials in admixturewith excipients suitable for the manufacture of aqueous suspensions.Such excipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

[0111] Oily suspensions may be formulated by suspending the activeingredient in a vegetable oil, for example arachis oil, olive oil,sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.The oily suspensions may contain a thickening agent, for examplebeeswax, hard paraffin or cetyl alcohol. Sweetening agents such as thoseset forth above, and flavoring agents may be added to provide apalatable oral preparation. These compositions may be preserved by theaddition of an anti oxidant such as ascorbic acid.

[0112] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

[0113] The pharmaceutical compositions of the invention may also be inthe form of oil in water emulsions. The oily phase may be a vegetableoil, for example olive oil or arachis oil, or a mineral oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

[0114] Syrups and elixirs may be formulated with sweetening agents, forexample glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative. and flavoringand coloring agents. Oral solutions can be prepared in combination with,for example, cyclodextrin, PEG and surfactants.

[0115] The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, axed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

[0116] The compounds of the present invention may also be administeredin the form of suppositories for rectal administration of the drug.These compositions can be prepared by mixing the drug with a suitablenonirritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols. Additionally, the compounds can be administered viaoculardelivery by means of solutions or ointments. Still further, transdermaldelivery of the subject compounds can be accomplished by means ofiontophoretic patches and the like.

[0117] For topical use, creams, ointments, jellies, solutions orsuspensions containing the compounds of the present invention areemployed. As used herein, topical application is also meant to includethe use of mouth washes and gargles.

[0118] The pharmaceutical compositions and methods of the presentinvention may further comprise other therapeutically active compounds asnoted herein, such as those applied in the treatment of the abovementioned pathological conditions.

[0119] Methods of Treating CCR9-Mediated Conditions or Diseases

[0120] In yet another aspect, the present invention provides methods oftreating or preventing a CCR9-mediated condition or disease byadministering to a subject having such a condition or disease atherapeutically effective amount of any compound of formula (I) above.Compounds for use in the present methods include those compoundsaccording to formula (I), those provided above as embodiments, thosespecifically exemplified in the Examples below, and those provided withspecific structures herein. The “subject” is defined herein to includeanimals such as mammals, including, but not limited to, primates (e.g.,humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice andthe like. In preferred embodiments, the subject is a human.

[0121] As used herein, the phrase “CCR9-mediated condition or disease”and related phrases and terms refer to a condition or diseasecharacterized by inappropriate, i.e., less than or greater than normal,CCR9 functional activity. Inappropriate CCR9 functional activity mightarise as the result of CCR9 expression in cells which normally do notexpress CCR9, increased CCR9 expression (leading to, e.g., inflammatoryand immunoregulatory disorders and diseases) or decreased CCR9expression. Inappropriate CCR9 functional activity might also arise asthe result of TECK secretion by cells which normally do not secreteTECK, increased TECK expression (leading to, e.g., inflammatory andimmunoregulatory disorders and diseases) or decreased TECK expression. ACCR9-mediated condition or disease may be completely or partiallymediated by inappropriate CCR9 functional activity. However, aCCR9-mediated condition or disease is one in which modulation of CCR9results in some effect on the underlying condition or disease (e.g., aCCR9 antagonist results in some improvement in patient well being in atleast some patients).

[0122] The term “therapeutically effective amount” means the amount ofthe subject compound that will elicit the biological or medical responseof a cell, tissue, system, or animal, such as a human, that is beingsought by the researcher, veterinarian, medical doctor or othertreatment provider.

[0123] Diseases and conditions associated with inflammation, immunedisorders, infection and cancer can be treated or prevented with thepresent compounds, compositions, and methods. In one group ofembodiments, diseases or conditions, including chronic diseases, ofhumans or other species can be treated with inhibitors of CCR9 function.These diseases or conditions include: (1) allergic diseases such assystemic anaphylaxis or hypersensitivity responses, drug allergies,insect sting allergies and food allergies, (2) inflammatory boweldiseases, such as Crohn's disease, ulcerative colitis, ileitis andenteritis, (3) vaginitis, (4) psoriasis and inflammatory dermatoses suchas dermatitis, eczema, atopic dermatitis, allergic contact dermatitis,urticaria and pruritus, (5) vasculitis, (6) spondyloarthropathies, (7)scleroderma, (8) asthma and respiratory allergic diseases such asallergic asthma, allergic rhinitis, hypersensitivity lung diseases andthe like, (9) autoimmune diseases, such as fibromyalagia, scleroderma,ankylosing spondylitis, juvenile RA, Still's disease, polyarticularjuvenile RA, pauciarticular juvenile RA, polymyalgia rheumatica,rheumatoid arthritis, psoriatic arthritis, osteoarthritis, polyarticulararthritis, multiple sclerosis, systemic lupus erythematosus, type Idiabetes, type II diabetes, glomerulonephritis, and the like, (10) graftrejection (including allograft rejection), (11) graft-v-host disease(including both acute and chronic), (12) other diseases in whichundesired inflammatory responses are to be inhibited, such asatherosclerosis, myositis, neurodegenerative diseases (e.g., Alzheimer'sdisease), encephalitis, meningitis, hepatitis, nephritis, sepsis,sarcoidosis, allergic conjunctivitis, otitis, chronic obstructivepulmonary disease, sinusitis, Behcet's syndrome and gout, (13) immunemediated food allergies such as Coeliac (Celiac) disease (14) pulmonaryfibrosis and other fibrotic diseases, and (15) irritable bowel syndrome.

[0124] In another group of embodiments, diseases or conditions can betreated with modulators and agonists of CCR9 function. Examples ofdiseases to be treated by modulating CCR9 function include cancers,cardiovascular diseases, diseases in which angiogenesis orneovascularization play a role (neoplastic diseases, retinopathy andmacular degeneration), infectious diseases (viral infections, e.g., HIVinfection, and bacterial infections) and immunosuppressive diseases suchas organ transplant conditions and skin transplant conditions. The term“organ transplant conditions” is means to include bone marrow transplantconditions and solid organ (e.g., kidney, liver, lung, heart, pancreasor combination thereof) transplant conditions.

[0125] Preferably, the present methods are directed to the treatment ofdiseases or conditions selected from inflammatory bowel diseaseincluding Crohn's disease and Ulcerative Colitis, allergic diseases,psoriasis, atopic dermatitis and asthma, autoimmune disease such asrheumatoid arthritis and immune-mediated food allergies such as Coelaicdisease.

[0126] Depending on the disease to be treated and the subject'scondition, the compounds and compositions of the present invention maybe administered by oral, parenteral (e.g., intramuscular,intraperitoneal, intravenous, ICV, intracisternal injection or infusion,subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal,sublingual, or topical routes of administration and may be formulated,alone or together, in suitable dosage unit formulations containingconventional non toxic pharmaceutically acceptable carriers, adjuvantsand vehicles appropriate for each rouse of administration. The presentinvention also contemplates administration of the compounds andcompositions of the present invention in a depot formulation.

[0127] In the treatment or prevention of conditions which requirechemokine receptor modulation an appropriate dosage level will generallybe about 0.001 to 100 mg per kg patient body weight per day which can beadministered in single or multiple doses. Preferably, the dosage levelwill be about 0.01 to about 25 mg/kg per day; more preferably about 0.05to about 10 mg/kg per day. A suitable dosage level may be about 0.01 to25 mg/kg per day, about 0.05 to 10 mg/kg per day, or about 0.1 to 5mg/kg per day. Within this range the dosage may be 0.005 to 0.05, 0.05to 0.5, 0.5 to 5.0, or 5.0 to 50 mg/kg per day. For oral administration,the compositions are preferably provided in the form of tabletscontaining 1.0 to 1000 milligrams of the active ingredient, particularly1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0,250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated. The compounds may beadministered on a regimen of 1 to 4 times per day, preferably once ortwice per day.

[0128] It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, hereditary characteristics, generalhealth, sex, diet, mode and time of administration, rate of excretion,drug combination, the severity of the particular condition, and the hostundergoing therapy.

[0129] In still other embodiments, the present methods are directed tothe treatment of allergic diseases, wherein a compound or composition ofthe invention is administered either alone or in combination with asecond therapeutic agent, wherein said second therapeutic agent is anantihistamine. When used in combination, the practitioner can administera combination of the compound or composition of the present inventionand a second therapeutic agent. Also, the compound or composition andthe second therapeutic agent can be administered sequentially, in anyorder.

[0130] In yet other embodiments, the present methods are directed to thetreatment of psoriasis wherein a compound or composition of theinvention is used alone or in combination with a second therapeuticagent such as a corticosteroid, a lubricant, a keratolytic agent, avitamin D₃ derivative, PUVA and anthralin.

[0131] In other embodiments, the present methods are directed to thetreatment of atopic dermatitis using a compound or composition of theinvention either alone or in combination with a second therapeutic agentsuch as a lubricant and a corticosteroid.

[0132] In further embodiments, the present methods are directed to thetreatment of asthma using a compound or composition of the inventioneither alone or in combination with a second therapeutic agent such as aβ2-agonist and a corticosteroid.

[0133] The compounds and compositions of the present invention can becombined with other compounds and compositions having related utilitiesto prevent and treat the condition or disease of interest, such asinflammatory conditions and diseases, including inflammatory boweldisease, allergic diseases, psoriasis, atopic dermatitis and asthma, andthose pathologies noted above. Selection of the appropriate agents foruse in combination therapies can be made one of ordinary skill in theart. The combination of therapeutic agents may act synergistically toeffect the treatment or prevention of the various disorders. Using thisapproach, one may be able to achieve therapeutic efficacy with lowerdosages of each agent, thus reducing the potential for adverse sideeffects.

[0134] The weight ratio of the compound of the present invention to thesecond active ingredient may be varied and will depend upon theeffective dose of each ingredient. Generally, an effective dose of eachwill be used. Thus, for example, when a compound of the presentinvention is combined with an NSAID the weight ratio of the compound ofthe present invention to the NSAID will generally range from about1000:1 to about 1:1000, preferably about 200:1 to about 1:200.Combinations of a compound of the present invention and other activeingredients will generally also be within the aforementioned range, butin each case, an effective dose of each active ingredient should beused.

EXAMPLES

[0135] Reagents and solvents used below can be obtained from commercialsources such as Aldrich Chemical Co. (Milwaukee, Wis., USA). ¹H-NMR wererecorded on a Varian Mercury 400 MHz NMR spectrometer. Significant peaksare tabulated in the order: multiplicity (s, singlet; d, doublet; t,triplet; q, quartet; m, multiplet) and number of protons. Massspectrometry results are reported as the ratio of mass over charge,followed by the relative abundance of each ion (in parenthesis). Intables, a single m/e value is reported for the M+H (or, as noted, M−H)ion containing the most common atomic isotopes. Isotope patternscorrespond to the expected formula in all cases. Electrospray ionization(ESI) mass spectrometry analysis was conducted on a Hewlett-Packard MSDelectrospray mass spectrometer using the HP1100 HPLC for sampledelivery. Normally the analyte was dissolved in methanol at 0.1 mg/mLand 1 microlitre was infused with the delivery solvent into the massspectrometer, which scanned from 100 to 1500 daltons. All compoundscould be analyzed in the positive ESI mode, using acetonitrile/waterwith 1% formic acid as the delivery solvent. The compounds providedbelow could also be analyzed in the negative ESI mode, using 2 mM NH₄OAcin acetonitrile/water as delivery system.

[0136] Compounds within the scope of this invention can be synthesizedas described below, using a variety of reactions known to the skilledartisan. A sample of useful routes to both the benzophenone andheteroaryl derived subunits and to fully elaborated sulfonamidemolecules of formula (I) within this claim are provided below. In thedescriptions of the syntheses that follow, some precursors were obtainedfrom commercial sources. These commercial sources include AldrichChemical Co., Acros Organics, Ryan Scientific Incorporated, OakwoodProducts Incorporated, Lancaster Chemicals, Sigma Chemical Co.,Lancaster Chemical Co., TCI-America, Alfa Aesar, Davos Chemicals, andGFS Chemicals.

[0137] Compounds of the invention can be prepared using conventionalsynthetic methodology. Examples of approaches that may be taken tosynthesize these compounds are shown below. Nonetheless, one skilled inthe art will recognize that alternative methods may be employed tosynthesize the target compounds of this invention, and that theapproaches described within the body of this document are notexhaustive, but do provide broadly applicable and practical routes tocompounds of interest.

[0138] Certain molecules claimed in this patent can exist in differentenantiomeric and diastereomeric forms and all such variants of thesecompounds are within the scope of the invention.

[0139] The detailed description of the experimental procedures used tosynthesize key compounds in this text lead to molecules that aredescribed by the physical data identifying them as well as by thestructural depictions associated with them.

[0140] Those skilled in the art will also recognize that during standardwork up procedures in organic chemistry, acids and bases are frequentlyused. Salts of the parent compounds are sometimes produced, if theypossess the necessary intrinsic acidity or basicity, during theexperimental procedures described within this patent.

[0141] Preparation of CCR 9 Modulators

[0142] The following examples are offered to illustrate, but not tolimit, the claimed invention.

[0143] Additionally, those skilled in the art will recognize that themolecules claimed in this patent may be synthesized using a variety ofstandard organic chemistry transformations.

[0144] Certain general reaction types employed widely to synthesizetarget compounds in this invention are summarized in the examples.Specfically, generic procedures for sulfonamide formation, pyridineN-oxide formation and 2-aminophenyl-arylmethanone synthesis viaFriedel-Crafts type approaches are given, but numerous other standardchemistries are described within and were employed routinely.

[0145] While not intended to be exhaustive, representative syntheticorganic transformations which can be used to prepare compounds of theinvention are included below.

[0146] These representative transformations include; standard functionalgroup manipulations; reduction such as nitro to amino; oxidations offunctional groups including alcohols and pyridines; aryl substitutionsvia IPSO or other mechanisms for the introduction of a variety of groupsincluding nitrile, methyl and halogen; protecting group introductionsand removals; Grignard formation and reaction with an electrophile;metal-mediated cross couplings including but not limited to Buckvald,Suzuki and Sonigashira reactions; halogenations and other electrophilicaromatic substitution reactions; diazonium salt formations and reactionsof these species; etherifications; cyclative condensations,dehydrations, oxidations and reductions leading to heteroaryl groups;aryl metallations and transmetallations and reaction of the ensuingaryl-metal species with an electrophile such as an acid chloride orWeinreb amide; amidations; esterifications; nuclephilic substitutionreactions; alkylations; acylations; sulfonamide formation;chlorosulfonylations; ester and related hydrolyses, and the like.

Example 1 General Procedure for the Preparation ofN-Aryl-benzenesulfonamides

[0147]

[0148] To the desired aniline (0.5 mmol) dissolved in pyridine andcooled in an ice-water bath was added a solution of an aryl sulfonylchloride (0.5 mmol) dissolved in cold pyridine. The reaction mixture wasthen heated to 60° C. with gentle shaking for 16 h. Evaporation of thesolvent with standard workup followed by either flash chromatography orreversed phase HPLC yielded the correspondingN-aryl-benzenesulfonamides.

Example 2 General Procedure for the Synthesis of(2-Amino-phenyl)-pyridinyl-methanones

[0149]

[0150] To 12.5 mL 1 M BCl₃ (12 mmol, 1.2 eq.) in methylene chloridestirred at 0° C. was added a solution of the desired haloaniline (10mmol, 1.0 eq.) in 15 mL of TCE drop wise over 20 minutes. After 10minutes the desired cyanopyridine (11 mmol, 1.1 eq.) was added followedby AlCl₃ (15 mmol, 1.5 eq.). The reaction was brought to RT, stirred foran hour then heated at 80-90° C. until all of the DCM was distilled off.The reaction mixture was then refluxed at 160° C. for 4 hours, cooled toRT and stirred overnight. 10 mL 3 M HCl were carefully added and themixture was refluxed at 120° C. for 2-3 hours while reaction progresswas monitored by LC/MS. The crude reaction was cooled to RT and 100 mLwater were added. The crude mixture was extracted with DCM (2×50 mL),the aqueous layer was set aside and the organic layer was back extractedwith 50 mL 1 M HCl (aq.). All aqueous layers were combined, brought topH 12 with 3 M NaOH (aq.) and extracted with DCM (4×50 mL). The DCMlayer was dried on Na₂SO₄, filtered and concentrated by rotaryevaporation. The crude product was washed liberally with Et₂O and driedunder vacuum, and further purified by conventional techniques such ascolumn chromatography when necessary.

Example 3 General Procedure for the Synthesis of SulfonamidePyridine-N-Oxides

[0151]

[0152] The desired N-Aryl-benzenesulfonamide (250 μmol) was dissolved in2 mL DCM and m-CPBA (1.0-1.5 eq) was then added. The reaction was shakenat RT and monitored by LC-MS. Additional m-CPBA was added as needed inaliquots until the reaction was complete. In most cases the reactionrequired 15-24 h rxn time. Standard workup led to the isolation of crudeproducts, which were purified by column chromatography.

Example 4 Synthesis of (2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone

[0153]

[0154] A solution of 4-chloroaniline (2.0 g, 16 mmol) in 30 mL of TCEwas added drop wise to a solution of BCl₃ (1M in DCM) (24 ml, 24 mmol)with ice bath cooling, over a period of 15 min and the reaction mixturestirred at that temperature for an additional 10 min. 4-Cyanopyridine(2.0 g, 19 mmol) and AlCl₃ (3.0 g, 22 mmol) were added with ice-watercooling. The solution was allowed to warm to room temperature andstirred for 30 min. The resulting solution was refluxed at 160° C. for 4h and stirred at room temperature overnight. The reaction mixture wasthen treated with 30 mL of 3N HCl and the mixture was refluxed at 110°C. for 1.5 h. The reaction mixture was allowed to cool down to roomtemperature and the solution was adjusted to pH 12 with 6N NaOH and thendiluted water and DCM. The resulting two layers were separated and theaqueous layer was extracted with DCM three times and the organic layerscombined and dried over sodium sulfate. After removal of the solvent,the resulting solid was washed with ether to yield(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone (2.8 g, 75%).

Example 5 Synthesis of(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-2-yl)methanone

[0155]

[0156] To 20 mL 1M BCl3 (20 mmol, 2.3 eq.) in DCM stirred at 0° C. wasadded a solution of 1.1 g 4-chloroaniline (8.6 mmol, 1.0 eq.) in 15 mLof TCE drop wise over five minutes. After 10 minutes 1.1 g of2-cyano-6-methyl pyridine (1.1 eq.) were added to the reaction mixtureand after 2 minutes 1.6 g AlCl₃ (12 mmol, 1.4 eq.) was added. After 5minutes the reaction was brought to RT, stirred for an hour then heatedat 160° C. for 17 hours. 100 mL 3M HCl were added and the reaction ismonitored by LC/MS. After 6 hours the reaction was removed from heat,cooled to RT and 300 mL water were added. The crude mixture wasextracted with DCM (1×500 mL), the aqueous layer was set aside and theorganic layer was back extracted with 300 mL 3M HCl (aq.). All aqueouslayers were combined, brought to pH 11 with 3M NaOH (aq.) and extractedwith DCM. The DCM layer was dried on Na₂SO₄, filtered and concentratedby rotary evaporation. Preparatory chromatography afforded the productas a cream colored solid which was converted to its HCl salt beforebeing characterized. ¹H NMR: δ (ppm): 2.83 (s, 3H), 7.32 (d, J=2.0 Hz,1H), 7.34 (d, J=1.6 Hz, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.82-7.85 (m, 2H),7.99 (t, J=7.6 Hz, H), 8.27 (d, J=7.6 Hz, 1H), 10.83 (s, 1H). MS:(M+H)/z=247.0

Example 6 Synthesis of(5-chloro-2-nitro-phenyl)-(6-chloro-pyridin-3-yl)-methanol

[0157]

[0158] A solution of 1.0 g 2-chloro-5-iodopyridine (4.1 mmol, 1.0 eq.)in 10 mL anhyd. THF was stirred at −40° C. to −50° C. After fiveminutes, 2.2 mL of 2.1 M ^(i)PrMgBr/THF (4.6 mmol, 1.1 eq.) were addeddrop wise over 1 minute and the reaction mixture is maintained at −40 to−50° C. for 30 minutes. 1.3 g 2-nitro-5-chlorobenzaldehyde (7.0 mmol,1.7 eq.) was then added and the reaction was maintained at −50° C. After1 hour, the reaction was allowed to warm to −10° C., and quenched with50 mL saturated brine after a further fifteen minutes. The crude productwas extracted with EtOAc, dried on Na₂SO₄ and concentrated by rotaryevaporation to yield desired product. MS: (M+H)/z=298.9

Example 7 Synthesis of(5-Chloro-2-nitro-phenyl)-(6-chloro-pyridin-3-yl)-methanone

[0159]

[0160] To (5-Chloro-2-nitro-phenyl)-(6-chloro-pyridin-3-yl)-methanol wasadded an excess (ca. 2 eq.) of PDC in DCM. The suspension was shaken atroom temperature overnight. The reaction was monitored by LC-MS, another1-2 eq. of PDC was added and the reaction was shaken for another 6hours. The crude product was filtered through Celite and purified byflash chromatography (silica gel, DCM). ¹H NMR (CDCl₃): δ (ppm): 7.50(d, J=2.4 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.68 & 7.70 (dd, J=8.8 Hz,2.0 Hz, 1H), 8.09-8.11 (m, 1H), 8.24 (d, J=8.8 Hz, 1H), 8.57 (d, J=2.0Hz, 1H. MS: (M+H)/z=296.9

Example 8 Synthesis of(2-Amino-5-chloro-phenyl)-(6-chloro-pyridin-3-yl)-methanone

[0161]

[0162] 3-(5-chloro-2-nitrophenyl)-pyridinylmethanone was added to amixture of concentrated HCl, DMF, SnCl₂ and heated at 130° C. Thereaction was monitored by LC/MS and removed from heat after 2 h. Thecrude reaction was treated with aq. K₂CO₃, extracted into DCM andconcentrated by rotary evaporation. The crude product was purified bypreparatory chromatography. MS: (M+H)/z=26.0

Example 9 Synthesis of N-(4-Chloro-phenyl)-2,2-dimethyl-propionamide

[0163]

[0164] To a solution of 4-chloroaniline (5.0 g, 39.2 mmol) in 25 mLpyridine was added 5.3 mL (43.1 mmol) of pivaloyl chloride and thereaction mixture stirred overnight at room temperature. The mixture waspoured into vigorously stirring 6M HCl, and the solids were collected byvacuum filtration, washed well with H₂O, and dried in vacuo to yield thetitle compound. 1H NMR (CDCl3) δ 7.47 (d, J=9.2 Hz, 2H) 7.30 (s, 1H)7.27 (d, J=8.8 Hz, 2H) 1.32 (s, 9H) MS (ES) m/z=212.1

Example 10 Synthesis ofN-[4-chloro-2-(hydroxy-pyridin-3-yl-methyl)-phenyl]-2,2-dimethyl-propionamide

[0165]

[0166] N-(4-Chloro-phenyl)-2,2-dimethyl-propionamide (3.0, 14.2 mmol)was dissolved in 15 mL THF in a dry 100 mL flask fitted with a rubbersepta and nitrogen inlet and cooled to 0° C. in ice water bath for 25minutes. A solution of 2.5M BuLi in hexane (17.0 mL, 42.6 mmol) wasadded and the mixture stirred for 45 minutes. To the thick yellowprecipitate that formed was added a solution ofpyridine-3-carboxaldehyde (3.03 g, 28.4 mmol) in 15 mL THF. The ice bathwas removed and the mixture was allowed to stir at room temperature for45 minutes and the reaction was quenched with 25 mL H₂O. The mixture wastransferred to a separating funnel, and the aqueous phase was discarded.The organics were dried in vacuo to yield product as an orange oil. 1HNMR (CDCl3) δ 8.85 (m, 1H) 8.54 (m, 1H) 8.42 (m, 1H) 8.10 (dd, J=8.8 Hz,2.8 Hz, 1H) 7.50 (d, J=8.0 Hz, 1H) 7.31 (m, 1H) 7.23 (m, 1H) 7.10 (m,1H) 5.85 (m, 1H) 1.70 (d, 1H) 1.08 (s, 9H); MS (ES) m/z=319.1 (MH)⁺

Example 11 Synthesis ofN-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-2,2-dimethyl-propionamide

[0167]

[0168]N-[4-chloro-2-(hydroxy-pyridin-3-yl-methyl)-phenyl]-2,2-dimethyl-propionamide(1.0 g, 3.14 mmol) was dissolved in 5 mL pyridine and treated with CrO₃(0.75 g, 7.5 mmol, 2.39 eq). The mixture was stirred under N₂ at roomtemperature for five hours, diluted with 20 mL 1:2 EtOAc/H₂O, andfiltered through Celite. The aqueous phase was separated and discarded,then the organics dried under vacuum yielding product (680 mg, 70%). 1HNMR (CDCl3) δ 11.06 (s, 1H) 8.92 (d, J=2.4 Hz, 1H) 8.84 (d, J=8.0 Hz,1H) 8.73 (d, J=9.2 Hz, 1H) 8.00 (d, J=8.0 Hz, 1H) 7.56 (dd, J=11.2 Hz,2.0 Hz, 1H) 7.48 (m, 2H) 1.36 (s, 9H) MS (ES) m/z=317.1 (MH)⁺

Example 12 Synthesis of (2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone

[0169]

[0170]N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-2,2-dimethyl-propionamide(0.65 g) was suspended in 5 mL of 70% H₂SO₄ and heated at 95° C. in oilbath overnight. After cooling to room temperature the solution was addeddrop wise with stirring to 20 mL of 40% NaOH solution placed in anice-water bath. The fine yellow precipitate formed was collected byvacuum filtration, washed well with water and dried under vacuum to give370 mg of product. 1H NMR (CDCl3) δ 8.84 (dd, J=2.4 Hz, 0.8 Hz, 1H) 8.77(dd, J=4.8 Hz, 2.0 Hz, 1H) 7.93 (dt, J=8.4 Hz, 2.0 Hz, 1H) 7.43 (m, 1H)7.35 (d, J=2.0 Hz, 1H) 7.25 (d, J=0.8 Hz, 1H) 6.71 (d, J=8.8 Hz, 1H)6.21 (s, 2H) MS (ES) m/z=233.0 (MH)⁺

Example 13 Synthesis of 2-methyl-isonicotinonitrile

[0171]

[0172] Dimethyl sulfate (18.3 mL, 192.4 mmol) was added to stirring2-picoline-N-oxide (20 g) over a 10 minute period. The reaction wasexothermic and the material quickly became homogeneous. The mixture washeated in a 60° C. oil bath for 2 hours, then the volatiles were removedunder vacuum and the pale yellow oil was diluted with 25 mL H₂O andadded drop wise over 10 minutes to 160 mL of 25% (w/v) KCN/H₂O. Afterstirring for 3.5 hours the yellow precipitate formed was collected byvacuum filtration and purified by column chromatography (EtOAc/Hexane)to yield 13.0 g of product (60%). 1H NMR (CDCl3) δ 8.66 (d, J=4.8 Hz,1H) 7.37 (s, 1H) 7.31 (d, J=4.4 Hz, 1H) 2.62 (s, 3H) 2.62 (s, 3H); MS(ES) m/z=119.0

Example 14 Synthesis of(2-amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone

[0173]

[0174] The title compound was prepared according to the generalprocedure for the Synthesis of (2-Amino-phenyl)-aryl-methanones, using4-chloro-phenylamine (1.8 g, 14.2 mmol) and 2-methyl-isonicotinonitrile(2.0 g, 16.9 mmol). 1H NMR (CDCl3) δ 8.64 (d, J=4.8 Hz, 1H) 7.28 (m, 3H)7.20 (d, J=6.0 Hz, 1H) 6.70 (d, J=12.4 Hz, 1H) 6.28 (s, 2H) 2.66 (s, 3H)MS (ES) m/z=247.0

Example 15 Synthesis of (2-amino-5-chloro-phenyl)-pyridin-2-yl-methanone

[0175]

[0176] To a solution of 2-bromopyridine (5 ml, 52 mmol) in Et₂O (60 ml)was added 40 ml of a n-butyllithium (1.6M in hexane, 64 mmol) drop wiseat −40° C. over 30 min under a nitrogen atmosphere. The resulting yellowsolution was stirred for a further 1 hr at −50° C. to −30° C. In aseparate flask, a solution of 2-amino-5-chlorobenzoic acid (2.05 g, 12mmol) in dry THF (90 ml), under nitrogen atmosphere and withice-cooling, was added in one portion to the solution prepared asdescribed above. The reaction mixture was stirred for 2 hrs at 0° C. andthen chlorotrimethylsilane (30 ml) was added at 0° C. with stirring. Thereaction mixture was allowed to warm to room temperature and 1 N HCl aq(100 ml) was added. The resulting two-phase system was separated. Theaqueous phase was adjusted to pH 12 with 6N NaOH solution and extractedwith ethyl acetate (2×150 ml). The combined organic extractions weredried over Na₂SO₄. After removal of solvent, the residue was purified bythe flash chromatography using ethyl acetate/hexane (1:4) as eluent.Crystallization of the product from Et₂O/hexane mixture gave 1.26 g(45%) of desired product as yellow solid. ¹H-NMR (DMSO-d₆, 500 MHz): δ6.90 (1H, d, J=9 Hz), 7.31 (1H, dd, J=9 and 2.5 Hz), 7.40 (2H, br), 7.53(1H, d, J=2.5 Hz), 7.61 (1H, m), 7.79 (1H, d, J=8 Hz), 8.03 (1H, m),8.69 (1H, m). MS: (ESI⁺): 233.2 (M+1).

Example 16 Synthesis of(2-Amino-5-chloro-phenyl)-(3-methyl-pyridin-4-yl)-methanone

[0177]

[0178] To a solution of 3-picoline (50 g, 0.48 mol) in glacial aceticacid (150 ml) was added hydrogen peroxide (25 ml) at RT. The mixture washeated to 90° C. for 3 hr. The mixture was cooled to RT and morehydrogen peroxide (18.5 ml) was added slowly. The mixture was againheated to 90° C. for 19 hr. The excess peroxide was carefully decomposedusing Pd—C (2.5 g) at 0° C. Pd—C was removed by filtration, and thefiltrate was concentrated and crude 3-methylpyridine-1-oxide waspurified by fractional distillation in vacuo.

[0179] A solution of 3-methylpyridine-1-oxide (10 g, 0.092 mol) inmethyl iodide (15 ml) was left at rt for 18 hr and the solid wasfiltered. The filtrate was diluted with diethyl ether and extracted withwater (40 ml). The solid was re-dissolved in the aqueous extract,1,4-dioxane (50 ml) was added, followed by potassium cyanide (15 g, 0.23mol) and the mixture was stirred at RT for 3 hr. The product wasextracted with chloroform. The chloroform layer was washed with water,brine and dried over sodium sulfate. The solvent was removed in vacuoand the crude product was purified by fractional distillation (61-62°C./0.2 mm) to yield a white low melting solid.

[0180] BCl₃ (24 ml, 1M in DCM, 0.024 mol) was added slowly to a solutionof 4-chloroaniline (2 g, 0.016 mol) in 30 ml of trichloroethylene over aperiod of 15 min. at 0° C. and stirred at this temperature for anadditional 10 min. 4-Cyano-3-methylpyridine (2.2 g, 0.019 mol) and AlCl₃(3 g, 0.022 mol) were added at 0° C. The solution was allowed to warm toRT and stirred for 30 min. The solution was then heated at 80-90° C. for1 hr. and the DCM was distilled off. The resulting solution was refluxedat 115° C. for 4 hr and stirred at RT overnight. 3N HCl (20 ml) wasadded and the mixture refluxed at 100° C. for 2 hr. The reaction mixturewas cooled to 0° C. and adjusted to pH-12 with 6N NaOH. The reactionmixture was extracted with DCM., and the DCM layer washed with water,brine and dried over Na₂SO₄. The solvent was removed, and the crude waspurified by column chromatography over silica gel to yield a yellowsolid.

Example 17 Synthesis of(2-Amino-4,5-difluoro-phenyl)-pyridin-4-yl-methanone

[0181]

[0182] Iron powder (28.1 g, 0.502 mol) was added as small portions to1,2-difluoro nitrobenzene (20.0 g, 0.126 mol) in methanol (200 ml) andheated to 60° C. Ammonium chloride (48.4 g, 0.91 mol) in water (100 ml)was added drop wise and the reaction mixture refluxed for 5 hr. Thereaction mixture was filtered over Celite and washed with methanol.Methanol was removed, and the aqueous layer was extracted withethylacetate, washed with brine, dried over sodium sulphate andconcentrated to yield 1,2-difluoro-4-aminobenzene (7 g, 43%).

[0183] BCl₃ (6.2 ml, 1M in DCM) was added drop wise to1,2-difluoro-4aminobenzene (0.5 g, 0.004 mol) in trichloroethylene (6.5ml) at 0° C. and this mixture stirred for 15 min. 4-Cyanopyridine (0.48g, 0.005 mol) was added and the solution was warmed to RT and stirredfor 30 min. The solution was then heated at 80-90° C. for 1 h. Theresulting solution was refluxed at 160° C. for 4 hr and stirred at RTover night. 3N HCl was added to the reaction mixture and refluxed at110° C. for 1.5 h. The reaction mixture was cooled to RT and made basic(pH=12) with 6N NaOH. The reaction mixture was diluted with water andDCM. The resulting two layers were separated and the aqueous layer wasextracted with DCM, dried over sodium sulphate and concentrated. Thecompound was purified by column chromatography using silica gel to yieldtitle compound (0.25 g, 27%).

Example 18 Synthesis of(6-Amino-2,3-difluoro-phenyl)-pyridin-4-yl-methanone

[0184]

[0185] To 3,4-Difluoroaniline (2.0 g, 0.0153 mol) and triethylamine (3.1g, 0.0307 mol) in dry benzene (100 ml) was added trimethylacetylchloride(2.3 g, 0.0184 mol) slowly at 0° C. and the reaction mixture stirred atRT overnight. The reaction mixture was then quenched with water andextracted with ethyl acetate. The organic layer was washed with water,brine, dried over sodium sulfate and concentrated. Compound wasrecrystallized from petroleum ether yielding 3.2 g, 98%.

[0186] This protected 3,4-difluoroaniline (2.7 g, 0.0126 mol) was takenin dry THF (25 ml) and under nitrogen t-butyllithium (2.02 g, 0.032 mol)was added drop wise at −78° C. Stirring was continued at −78° C. for 2h. 4-Pyridine carboxaldehyde (3.55 g, 0.033 mol) dissolved in dry THF(10 ml) was added slowly. The reaction mixture was warmed to roomtemperature and stirred over night. The reaction mixture was thenquenched with water and extracted with ether. The organic layer waswashed with brine, dried over sodium sulfate and concentrated. Compoundwas purified by column chromatography to yield carbinol (2.6 g, 65%).

[0187] To carbinol (2.6 g, 0.0031 mol) in 17.3 ml of pyridine was addeda suspension of chromium trioxide (0.705 g, 0.007 mol) in pyridine (6.0ml) under a nitrogen atmosphere. The resulting mixture was allowed tostir at RT over night. The reaction mixture was poured into water andextracted with ether. The ether extract was washed with brine, driedover sodium sulfate and concentrated. The compound was purified bycolumn chromatography to yield the protected precursor to the titlecompound (1.7 g, 65.8%).

[0188] To this pivaloyl protected amino ketone (1.7 g, 0.0053 mol) wasadded 70% sulfuric acid (14.6 ml) and the reaction mixture heated to95-100° C. overnight. The reaction mixture was basified by using 10%sodium hydroxide and extracted with dichloromethane. The organic layerwas washed with water, brine, dried over sodium sulfate andconcentrated. The product obtained was purified by column chromatographyto yield title compound (0.58 g, 46.4%).

Example 19 Synthesis of(2-Amino-5-chloro-4-methoxy-phenyl)-pyridin-4-yl-methanone

[0189]

[0190] 5-Nitro-2-chloro aniline (50.0 g, 0.289 mol) in 30% sulfuric acid(300 ml) was stirred at RT for 2 h. Sodium nitrite (21.0 g, 0.304 mol)in water (50 ml) was added slowly at 0° C. After 15 mins, this solutionwas added slowly to dilute sulfuric acid (50%, 250 ml) at 110° C.Stirring was continued for 15 min. The reaction mixture was cooled toRT, ice water was added, extracted with ethylacetate, washed with water,brine and dried over Na₂SO₄. The phenol product obtained uponconcentration was purified by column chromatography. Yield 12.0 g,24.0%.

[0191] K₂CO₃ (23.84 g, 0.172 mol) was added to 2-chloro-5-nitrophenol(10.0 g, 0.058 mol) in acetonitrile (100 ml) at RT. After cooling to 0°C., methyl iodide (19.6 g, 0.138 mol) was added slowly and the reactionmixture stirred at RT overnight. Water (100 ml) was added and theaqueous layer extracted with ethyl acetate. The organic layer was washedwith water, brine and dried over Na₂SO₄. The product obtained uponconcentration was purified by column chromatography to yield the anisole(6.0 g, 55.55%).

[0192] 2-Chloro-5-nitro anisole (6.0 g, 0.032 mol) in MeOH (45 ml) wasadded slowly to stannous chloride (15.1 g, 0.08 mol) in conc. HCl (110ml) at 40° C. and the temperature was slowly raised to 50° C. Stirringwas continued for 2 h. After cooling to RT, the reaction mixture wasbasified with 50% NaOH solution, extracted by ethyl acetate, washed withwater, then brine and dried over Na₂SO₄. 3-Methoxy-4-chloroaniline wasobtained upon concentration and was purified further by columnchromatography. Yield: 4.0 g, 79.36%.

[0193] To 3-Methoxy-4-chloroaniline (2.0 g, 0.0126 mol) intrichloroethylene (30 ml) was added BCl₃ (2.18 g, 1 M solution in DCM,0.0188 mol) at 0° C. After stirring for 10 min, 4-cyanopyridine (1.6 g,0.0153 mol) and AlCl₃ (2.35 g, 0.018 mol) were added and the temperaturewas raised to RT, with further stirring for 30 min. The temperature wasraised further to 85° C. and maintained at the same temperature for 1 h.DCM was distilled off and the solution was stirred at 115° C. for 4 hand then at RT over night. 3N HCl was added at RT and the reactionmixture refluxed for 1.5 h. The reaction mixture was allowed to cool andmade basic using NaOH (6 N), diluted with water and extracted with DCM,washed with water, brine and dried over Na₂SO₄. The crude title compoundwas obtained upon concentration and was purified by columnchromatography. Yield: 0.50 g, 15%.

Example 20 Synthesis of(2-Amino-5-chloro-phenyl)-pyrimidin-4-yl-methanone

[0194]

[0195] To 4-Methyl pyrimidine (5.0 g, 0.053 mol) in pyridine (55 ml) wasadded selenium dioxide (8.82 g, 0.079 mol) at RT with stirring. Thereaction mixture was stirred at 55° C. for 2 h and at 80° C. for 3.5 hr.After cooling to RT and stirring over night, the reaction mixture wasfiltered and the residue was washed with pyridine. The combined pyridinesolution was concentrated and the carboxylic acid obtained was washedwith water to remove traces of selenium dioxide. Yield: 5.3 g, 80.5%.

[0196] To Pyrimidine-4-carboxylic acid (5.0 g, 0.04 mol) in methanol(170 ml) was added conc. HCl (2 ml) at RT. After refluxing overnight,the reaction mixture was cooled to RT and neutralized with 10% sodiumbicarbonate solution and concentrated. The ester was extracted withdiethyl ether, dried over Na₂SO₄ and concentrated to get the methylester as a yellow solid, yield: 3.3 g, 57.55%.

[0197] Trimethyl acetylchloride (11.30 g, 0.093 mol) was added to abenzene (500 ml) solution of triethylamine (15.75 g, 0.155 mol) and4-chloroaniline (10.0 g, 0.078 mol) at 0° C. The reaction mixture waswarmed to RT and stirred for 3 h. The reaction mixture was then quenchedwith water, extracted with ethyl acetate, washed with water, brinesolution and dried over Na₂SO₄. The solid product obtained wascrystallized from pet ether. Yield: 14.0 g, 84.43%.

[0198] To N-(4-chlorophenyl)-2,2-dimethyl propanamide (3.5 g, 0.0165mol) in THF (50 ml) at 0° C. was added n-butyl lithium in hexane (2.64g, 1.2 M, 0.041 mol). Stirring was continued at 0° C. for 2 h, thereaction then cooled to −70° C., pyrimidine-4-methyl carboxylate (3.18g, 0.023 mol) in THF (25 ml) was then added slowly and the solution waswarmed to RT and stirred overnight. Diethyl ether (50 ml) and water (50ml) were added and the organic layer was separated. The aqueous layerwas further extracted with ether. The combined ether layers were washedwith water, brine and dried over Na₂SO₄. The product obtained uponconcentration was purified by column chromatography. Yield: 1.7 g,32.69%.

[0199] The protected amino ketone (1.7 g, 0.0054 mol) in sulfuric acid(10 ml, 70%) was heated at 95° C. over night. The reaction mixture wascooled to RT and basified with 10% NaOH, extracted with DCM, washed withwater, brine and dried over Na₂SO₄. The product obtained uponconcentration was purified by column chromatography using basic aluminato yield title compound (0.20 g, 16%).

Example 21 Synthesis of(6-Amino-3-chloro-2-methoxy-phenyl)-pyridin-4-yl-methanone

[0200]

[0201] 5-Nitro-2-chloro aniline (50.0 g, 0.289 mol) in 30% sulfuric acid(300 ml) was stirred at RT for 2 h. Sodium nitrite (21.0 g, 0.304 mol)in water (50 ml) was added slowly at 0° C. and maintained at thistemperature for 15 min. This diazotized solution was added slowly todilute sulfuric acid (50%, 250 ml) at 110° C. Stirring was continued for15 min. After cooling to RT, ice water was added, the mixture extractedwith ethylacetate, washed with water, brine and dried over Na₂SO₄. Theproduct obtained upon concentration was purified by columnchromatography. Yield 12.0 g, 24.0%.

[0202] To K₂CO₃ (23.84 g, 0.172 mol) and 2-chloro-5-nitrophenol (10.0 g,0.0576 mol) in acetonitrile (100 ml) was added methyl iodide (19.60 g,0.138 mol) at 0° C. The reaction mixture was warmed to RT and stirredovernight. Water was added and extracted with ethyl acetate. The organiclayer was washed with water, brine and dried over Na₂SO₄. The productobtained upon concentration was purified by column chromatography.Yield: 6.0 g, 55.55%.

[0203] 2-Chloro-5-nitro anisole (6.0 g, 0.032 mol) in MeOH (45 ml) wasadded slowly to stannous chloride (15.1 g, 0.08 mol) in conc. HCl (110ml) at 40° C. and the temperature was slowly raised to 50° C. Stirringwas continued for 2 h, the reaction cooled to RT, basified with 50% NaOHsolution and extracted by ethyl acetate. The organic layer was washedwith water, brine and dried over Na₂SO₄. The product obtained uponconcentration was purified by column chromatography. Yield: 4.0 g,79.36%.

[0204] To triethylamine (3.83 g, 0.037 mol) and 3-methoxy-4-chloroaniline (3.0 g, 0.0190 mol) in benzene (50 ml) was addedtrimethylacetylchloride (2.75 g, 0.022 mol) slowly at 0° C. Thetemperature was raised to RT and stirred overnight. The reaction mixturewas added to ice and extracted with ethyl acetate. The organic layer waswashed with water, brine, dried over Na₂SO₄ and concentrated. Yield: 3.7g, 80.43%.

[0205] To N-pivaloyl-3-methoxy-4-chloroaniline (1.50 g, 0.0062 mol) inTHF (30 ml) was added n-butyl lithium (1.0 g, 0.0156 mol) at 0° C. andthe reaction stirred for 2 hr. After cooling to −70° C., methylisonicotinate (1.3 g, 0.0094 mol) in THF (12 ml) was added slowly. Thereaction was warmed to rt and stirred overnight and then quenched withwater and extracted with ether. The water layer was further extractedand the combined ether layers were washed with water, brine and driedover Na₂SO₄. The product obtained upon concentration was purified bycolumn chromatography. Yield 0.50 g, 23.25%.

[0206] The protected ketone from step 5 (0.500 g, 0.0014 mol) wassuspended in concentrated HCl (5 ml) at RT, then the temperature wasraised to 95° C. and the mixture stirred over night. The mixture wascooled to RT, basified with 20% NaOH solution and extracted with DCM.The combined organic layer was washed with water, brine and dried overNa₂SO₄. The product obtained upon concentration was purified by columnchromatography using basic alumina to yield title compound (0.140 g,37.33%).

Example 22 Synthesis of(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone

[0207]

[0208] To a solution of 2-picoline (50 g, 0.48 mol) in glacial aceticacid (150 ml) was added hydrogen peroxide (25 ml) at RT. The mixture washeated to 90° C. for 3 hr. The mixture was cooled to RT and morehydrogen peroxide (18.5 ml) was added slowly. The mixture was againheated to 90° C. for 19 hr. The excess peroxide was cautiouslydecomposed using Pd—C (2.5 g) at 0° C. Pd—C was filtered, the filtratewas concentrated and the crude 2-methylpyridine-1-oxide was purified byfractional distillation under vacuum. Yield: 40 g, 69%.

[0209] A solution of 2-methylpyridine-1-oxide (10 g, 0.092 mol) inmethyl iodide (15 ml) was stirred at RT for 18 hr. The solid wasfiltered. The filtrate was diluted with diethyl ether, extracted withwater (40 ml). The solid was re-dissolved in the aqueous layer,1,4-dioxane (50 ml) was added, followed by potassium cyanide (15 g, 0.23mol). The mixture was stirred at RT for 3 hr. The product was extractedwith chloroform. The chloroform layer was washed with water, brine anddried over sodium sulfate. The solvent was removed under vacuo and thecrude material was purified by fractional distillation (61-62° C./0.2mm) to yield a white low melting solid (6 g, 35%).

[0210] BCl₃ (24 ml, 1M in DCM, 0.024 mol) was added slowly to a solutionof 4-chloroaniline (2 g, 0.016 mol) in 30 ml of trichloroethylene over aperiod of 15 min. at 0° C. and stirred at this temperature for anadditional 10 min. 4-Cyano-2-methylpyridine (2.2 g, 0.019 mol) and AlCl₃(3 g, 0.022 mol) were added at 0° C. The solution was warmed to RT andstirred for 30 min. The solution was then heated at 80-90° C. for 1 hand the DCM was distilled off. The resulting solution was refluxed at115° C. for 4 hr and stirred at RT over night. 3N HCl (20 ml) was addedto the mixture and refluxed at 100° C. for 2 hr. The reaction mixturewas cooled to 0° C. and was made basic (pH—12) with 6N NaOH and thereaction mixture was extracted with DCM. The DCM layer was washed withwater, brine and dried over Na₂SO₄. The solvent was removed, the crudewas purified by column chromatography (silica gel) to yield titlecompound as yellow solid (1.55 g, 40%).

Example 23 Synthesis of (2-Amino-4-chloro-phenyl)-pyridin-4-yl-methanone

[0211]

[0212] To BCl₃ (1M in DCM) (24 mL, 24 mmol), cooled to 0° C., a solutionof 3-chloroaniline (2.0 g, 16 mmol) in 30 mL of TCE was added drop wiseover a period of 15 min and the mixture stirred at that temperature foran additional 10 min. 4-cyanopyridine (2.0 g, 19 mmol) and AlCl₃ (3.0 g,22 mmol) was added under ice-water cooling. The solution was allowed towarm to rt and stirred for 30 min. The solution was then heated at80-90° C. for 1 h and the DCM distilled off. The resulting solution wasrefluxed at 160° C. for 4 h and stirred at rt overnight. 3N HCl (20 mlapprox.) was added to the reaction mixture and then refluxed at 110° C.for 1.5 hr. The reaction mixture was cooled to rt and the solution wasmade basic (pH 12) with 6N NaOH. The reaction mixture was diluted withwater and DCM. The resulting two layers were separated and the aqueouslayer was extracted with DCM (3×1 50 mL), and dried (Na₂SO₄). Afterremoval of solvent, the solid was washed with Et₂O to give 650 mg (24%)of desired product.

Example 24 Synthesis of (2-Amino-3-chloro-phenyl)-pyridin-4-yl-methanone

[0213]

[0214] To a solution of BCl₃ (1M in DCM) (24 mL, 24 mmol), cooled to 0°C., was added a solution of 2-chloroaniline (2.0 g, 16 mmol) in 30 mL ofTCE drop wise over a period of 15 min and the reaction stirred for anadditional 10 min. 4-cyanopyridine (2.0 g, 19 mmol) and AlCl₃ (3.0 g, 22mmol) were added under ice-water cooling. The solution was allowed towarm to rt and stirred for 30 min. The solution was then heated at80-90° C. for 1 h and the DCM distilled off. The resulting solution wasrefluxed at 160° C. for 4 h and stirred at rt overnight. 3N HCl (20 mlapprox.) was added to the reaction mixture and refluxed at 110° C. for1.5 hr. The reaction mixture was cooled to rt and the solution was madebasic (pH 12) with 6N NaOH. The reaction mixture was diluted with waterand DCM. The resulting layers were separated and the aqueous layer wasextracted with DCM (3×1 50 mL), and the combined organic layers dried(Na₂SO₄). After removal of solvent, the solid was washed with Et₂O togive 600 mg (21%) of desired product.

Example 25 Synthesis of (2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone

[0215]

[0216] To a solution of BCl₃ (1M in DCM) (18 mL, 18 mmol), cooled to 0°C., was added drop wise over a period of 15 min a solution of4-bromoaniline (2 g, 11.6 mmol) in 30 mL of TCE and the mixture stirredfor an additional 10 min. 4-cyanopyridine (2.0 g, 19 mmol) and AlCl₃(3.0 g, 22 mmol) were added under ice-water cooling. The solution waswarmed to rt and stirred for 30 min. The solution was then heated at80-90° C. for 1 h and the DCM distilled off. The resulting solution wasrefluxed at 160° C. for 4 h and stirred at rt overnight. 3N HCl (20 mlapprox.) was added to the reaction mixture and refluxed at 110° C. for1.5 hr. The reaction mixture was allowed to cool down and the solutionwas made basic (pH 12) with 6N NaOH. The reaction mixture was dilutedwith water and DCM. The resulting two layers were separated and theaqueous layer was extracted with DCM (3×1 50 mL), and the combinedorganic layers dried (Na₂SO₄). After removal of solvent, the solid waswashed with Et₂O to give 1.050 g of desired product.

Example 26 Synthesis of (2-amino-5-fluoro-phenyl)-pyridin-4-yl-methanone

[0217]

[0218] To a solution of BCl₃ (1M in DCM) (27 mL, 27 mmol), cooled to 0°C., was added drop wise over a period of 15 min a solution of4-fluoroaniline (2.0 g, 18 mmol) in 30 mL of TCE and the mixture stirredat that temperature for an additional 10 min. 4-cyanopyridine (2.6 g, 25mmol) and AlCl₃ (3.0 g, 22 mmol) were added under ice-water cooling. Thesolution was allowed to warm to rt and then stirred for 30 min. Thesolution was then heated at 80-90° C. for 1 h and the DCM distilled off.The resulting solution was refluxed at 160° C. for 4 h and stirred at rtovernight. 3N HCl (20 ml approx.) was added to the reaction mixture andrefluxed at 110° C. for 1.5 hr. The reaction mixture was allowed to cooldown and the solution was made basic (pH 12) with 6N NaOH. The reactionmixture was diluted with water and DCM. The resulting two layers wereseparated and the aqueous layer was extracted with DCM (3×150 mL), andthe combined organic layers dried (Na₂SO₄). After removal of solvent,the solid was washed with Et₂O to give 1.05 g (27%) of desired product.

Example 27 Synthesis of(2-Amino-5-chloro-phenyl)-(1-methyl-1H-imidazol-2-yl)-methanone

[0219]

[0220] To a solution of ^(n)BuLi (0.0730 mol) in hexane was addedN-methyl imidazole (0.0608 mol) drop wise at −40° C. over 30 min under anitrogen atmosphere. The resulting yellow solution was stirred for afurther 3 hr at rt, and then refluxed for 1 h. 2-amino-5-chlorobenzoicacid (1.74 g, 0.01014 mole) in dry ether (60 ml) was then added to thereaction mixture. The reaction mixture was stirred overnight at rt. Tothe reaction mixture was added saturated NH₄Cl solution and theresulting mixture extracted with ethyl acetate (2×150 ml). The combinedorganic layers were dried over Na₂SO₄. After removal of solvent, theresidue was purified by the flash chromatography using ethylacetate/hexane (1:4) as eluent. Crystallization of the product fromEt₂O/hexane mixture gave 300 mg (13.7%) of product as yellow solid.

Example 28 Synthesis of (2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-3-ylmethanone

[0221]

[0222] Trimethylacetyl chloride (35 g) was added drop wise to a solutionof 4-chloroaniline (31.9 g) in dry pyridine and the reaction was stirredunder nitrogen overnight. About half of the pyridine was removed byrotary evaporation, then the mixture was treated with 6M hydrochloricacid and extracted with ethyl acetate. The extracts were washed withsaturated aqueous NaHCO3 and with water, then were dried (MgSO4),filtered and concentrated by rotary evaporation. The resultingcrystalline product was vacuum filtered and dried at high vacuum toconstant weight, resulting in a good yield ofN-(4-chloro-phenyl)-2,2-dimethyl-propionamide as fine needles. EDC (10g) and 2-methyl-nicotinic acid (7.15 g) were magnetically stirred inacetonitrile-THF with N,O-dimethylhydroxylamine hydrochloride (9.75 g)and triethylamine (25 mL). After stirring overnight at ambienttemperature, the resulting white suspension was added to ice water andextracted with ethyl acetate (3×100 mL). The extracts were dried,filtered, and concentrated to give a light amber oil.

[0223] To a magnetically stirred solution ofN-(4-chloro-phenyl)-2,2-dimethyl-propionamide (3.16 g, 14.9 mmol) in dryTHF was added 2.5M n-butyllithium in hexane at −40° C. and the mixturewas stirred at 0° C. for 2 h and a suspension of white solid resulted. Asolution of the Weinreb amide (1.80 g, 10.0 mmol) in dry THF was addeddrop wise and the reaction was stirred at ambient temp overnight. Themixture was diluted with water and extracted with ethyl acetate and theorganic layer was dried (MgSO4), filtered and concentrated.Chromatography on silica gel (20-30% EtOAc/Hexane) provided the desiredN-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-2,2-dimethyl-propionamideas a waxy bright yellow solid (2.28 g, 6.89 mmol): ¹H NMR (CDCl3) δ11.71 (s, 1H, NH), 8.82 (d, 1H, J=9.2 Hz), 8.67 (dd, 1H, J=4.8 Hz, J=1.8Hz), 7.55 (m, 2H), 7.28 (d, 1H, J=2.5 Hz), 7.25 (m, 1H), 2.54 (s, 3H),1.39 (s, 9H).

[0224] TheN-[4-chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-2,2-dimethyl-propionamideintermediate (2.28 g, 6.89 mmol) was magnetically stirred with 70%sulfuric acid and heated at 75° C. and progress of the solvolysis wasmonitored by LC/MS. The reaction was allowed to cool to ambienttemperature, and was washed with ether-hexane to remove oily byproducts.The acidic aqueous layer was cooled in an ice bath and aqueous NaOH wasadded drop wise to basify the mixture. The product was extracted withethyl acetate and the extracts were washed with saturated aqueous NaHCO3(2×100 mL), with saturated aqueous sodium chloride, dried (MgSO4),filtered and concentrated. The bright yellow product crystallized onstanding: ¹H NMR (CDCl3) δ 8.54 (dd, 1H, J=5.2 Hz, J=1.6 Hz), 7.45 (dd,1H, J=7.6 Hz, J=1.5 Hz), 7.15 (m, 2H), 7.00 (d, 1H, J=2.6 Hz), 6.61 (d,1H, J=9.1 Hz), 6.39 (br s, 2H), 2.42 (s, 3H).

Example 29 Synthesis of(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone

[0225]

[0226] The title compound was prepared using procedures described abovefor the synthesis of2-amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone.

Example 30 Synthesis ofN-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-oxazol-5-yl-benzenesulfonamide

[0227]

[0228] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 116 mg of(2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 122 mg4-oxazol-5-yl-benzenesulfonyl chloride. Purification by purification byreversed phase HPLC gave pure product. ¹H-NMR (400 MHz, CDCl₃): δ 7.21(dd, H, J=1.5, 4.4 Hz), 7.30 (d, 1H, J=2.5 Hz), 7.42 (s, 1H), 7.54 (dd,1H, J=2.5, 8.8 Hz), 7.61 (d, 2H, J=8.4 Hz), 7.77 (s, 1H), 7.78 (d, 2H,J=8.4 Hz), 7.95 (s, 1H), 8.69 (d, 2H, J=5.8 Hz), 10.06 (br, 1H). MS: m/z440.9 (M⁺+1).

Example 31 Synthesis of4-tert-Butyl-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

[0229]

[0230] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 116 mg of(2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 116 mg of4-tert-Butyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 1.25(s, 9H), 7.02 (d, 1H, J=8.4 Hz). 7.44 (m, 3H), 7.66 (d, 2H, J=8.4), 7.79(d, 1H, J=2.4 Hz), 8.11 (d, 2H, J=6.4), 8.88 d, 2H, J=6.0 Hz), 10.51 (s,1H). MS: m/z 429.9 (M⁺+1).

Example 32 Synthesis of4-tert-Butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

[0231]

[0232]4-tert-Butyl-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide(107 mg, 0.25 mmol) was dissolved in 4 mL DCM and m-chloroperoxybenzoic(0.26 mmol) was added. The mixture was stirred at room temperature for16 h. The solvent was evaporated on a rotary evaporator and the productwas purified by reversed phase HPLC to yield title compound. ¹H-NMR (400MHz, CDCl₃): δ 1.24 (s, 9H), 7.32-7.4 (m, 5H), 7.52 (dd, 1H, J=8.8, Hz,2.4 Hz), 7.63 (d, 2H, J=8.8 Hz), 7.74 (d, 1H, J=8.8 Hz), 8.18 (d, 2H,J=7.6 Hz), 9.60 (s, 1H). MS: m/z 445.9 (M⁺+1).

Example 33 Synthesis ofN-[4-Chloro-2-(pyridine-2-carbonyl)-phenyl]-4-methoxy-benzenesulfonamide

[0233]

[0234] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 116 mg of(2-Amino-5-chloro-phenyl)-pyridin-2-yl-methanone and 101 mg of4-methoxy-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 3.75 (s,3H), 6.76 (m, 2H, 7.45 (m, 2H), 7.63 (m, 2H), 7.71 (d, 1H, J=8.8 Hz),7.78 (m, 1H), 7.88 (m, 2H), 8.64 (m, 1H), 10.24 (s, 1H). MS: m/z 403.9(M⁺+1).

Example 34 Synthesis ofN-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-methoxy-benzenesulfonamide

[0235]

[0236] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 116 mg of(2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 101 mg of4-methoxy-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 3.74 (s,3H), 6.77 (d, 2H, J=8.8 Hz), 7.21 (m, 2H), 7.27 (d, 1H, J=2 Hz), 7.52(dd, 1H, J=8.8 Hz, 2.8 Hz), 7.63 (m, 2H), 7.76 (d, 1H, J=8.8 Hz), 8.76(d, 2H, J=5.6 Hz), 9.88 (s, 1H). MS: m/z 403.9 (M⁺+1).

Example 35 Synthesis ofN-[4-Bromo-2-(pyridine-4-carbonyl)-phenyl]-4-methoxy-benzenesulfonamide

[0237]

[0238] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 138 mg of(2-amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 101 mg of4-methoxy-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 3.69 (s,3H), 6.68 (d, 2H, J=8.8 Hz), 7.36-7.47 (m, 4H), 7.46, 7.55-7.69 (m, 5H),9.65 (s, 1H). MS: m/z 448.3 (M⁺+1).

Example 36 Synthesis of4-tert-Butyl-N-[4-fluoro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

[0239]

[0240] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 108 mg of(2-Amino-5-fluoro-phenyl)-pyridin-4-yl-methanone and 116 mg of4-tert-butyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 1.25(s, 9H), 6.98 (dd, 1H, J=8.8 Hz, 3.2 Hz), 7.30-7.38 (m, 3H), 7.43 (m,2H), 7.62 (m, 2H), 7.80 (dd, 1H, 9.2 Hz, 4.8 Hz), 8.82 (d, 2H, 4.8 Hz),9.82 (s, 1H). MS: m/z 413.5 (M⁺+1).

Example 37 Synthesis ofN-[4-Bromo-2-(pyridine-4-carbonyl)-phenyl]4-tert-butyl-benzenesulfonamide

[0241]

[0242] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 138 mg of(2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 116 mg of4-tert-butyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 1.27(3, 9H), 7.41 (m, 3H), 7.50 (dd, 2H, J=4.8 Hz, 1.6 Hz), 7.67-72 (m, 4H),8.85 (d, 2H, J=6 Hz), 10.19 (s, 1H). MS: m/z 473.9 (M⁺+1).

Example 38 Synthesis of4-tert-Butyl-N-[5-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

[0243]

[0244] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 116 mg of(2-amino-4-chloro-phenyl)-pyridin-4-yl-methanone and 116 mg of4-tert-butyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 1.30(s, 9H), 7.04 (d, 1H, J=8.4 Hz), 7.25 (d, 1H, J=8.4 Hz), 7.45-7.52 (m,4H), 7.74 (dd, 2H, J=8.8 Hz, 1.6 Hz), 7.52 (dd, 2H, J=4.4 Hz, 1.6 Hz),7.78 (m, 2H), 7.84 (d, 1.6 Hz), 8.84 (d, 2H, J=5.6 Hz), 10.61 (s, 1H).MS: m/z 429.0 (M⁺+1).

Example 39 Synthesis ofN-[4-Bromo-2-(pyridine-4-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide

[0245]

[0246] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 138 mg of(2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 130 mg of4-trifluoromethoxy-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ7.21 (d, 2H, J=8.8 Hz), 7.35 (m, 2H), 7.45 (s, 1H), 7.70 (m, 2H), 7.83(m, 2H), 8.82 (dd, 2H, J=4.8 Hz, 1.6 Hz), 10.21 (s, 1H). MS: m/z 502.3(M⁺+1).

Example 40 Synthesis of4-Bromo-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

[0247]

[0248] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 116 mg of(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 122 mg of4-bromo-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 7.21 (d,1H, J=2.4 Hz), 7.49-7.61 (m, 5H), 7.73 (d, 1H, J=8.8 Hz), 8.86 (dd, 2H,J=4.4 Hz, 1.2 Hz), 10.00 (s, 1H). MS: m/z 451.9 (M⁺+1)

Example 41 Synthesis ofN-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-3-cyano-benzenesulfonamide

[0249]

[0250] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 116 mg of(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 100 mg of3-cyano-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 7.36 (d,1H, J=2.4 Hz), 7.57-7.62 (m, 4H), 7.68 (d, 1H, J=8.8 Hz), 7.80 (m, 1H),8.04 (m, 2H), 8.90 (dd, 2H, J=4.8 Hz, 1.6 Hz), 10.3 (b, 1H). MS: m/z398.8 (M⁺+1).

Example 42 Synthesis ofN-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-methanesulfonyl-benzenesulfonamide

[0251]

[0252] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 116 mg of(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 127 mg of4-methanesulfonyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ3.06 (s, 3H), 7.31 (d, 1H, J=2.0 Hz), 7.45 (m, 2H), 7.58 (dd, 1H, J=8.8Hz, 2.8 Hz), 7.99 (b, 4H), 8.88 (dd, 2H, J=4.8 Hz, 1.6 Hz), 10.29 (b,1H). MS: m/z 451.9 (M⁺+1).

Example 43 Synthesis of4-tert-Butyl-N-[4-chloro-2-(pyrimidine-4-carbonyl)-phenyl]-benzenesulfonamide

[0253]

[0254] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 116 mg of(2-Amino-5-chloro-phenyl)-pyrimidin-4-yl-methanone and 116 mg of4-tert-butyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 1.23(s, 9H), 7.40 (d, 2H, J=8.4 Hz), 7.51 (dd, 1H, J=8.8 Hz, 2 Hz),7.71-7.80 (m, 6H), 9.03 (d, 1H, J=4.8 Hz), 9.33 (d, 1.2 Hz), 10.91 (b,1H). MS:m/z 434.0 (M⁺+1).

Example 44 Synthesis of Biphenyl-4-sulfonic acid[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-amide

[0255]

[0256] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 116 mg of(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 126 mg ofbiphenyl-4-sulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 7.24 (m, 1H),7.36 (m, 2H), 7.42 (m, 5H), 7.56 (m, 3H), 7.77-7.84 (m, 3H), 8.73 (d,2H, J=4.4 Hz), 10.01 (s, 1H). MS: m/z 449.0 (M⁺+1).

Example 45 Synthesis of4-tert-Butyl-N-[4-chloro-2-(3-methyl-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

[0257]

[0258] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 123 mg of(2-Amino-5-chloro-phenyl)-(3-methyl-pyridin-4-yl)-methanone and 116 mgof 4-tert-butyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ1.32 (s, 9H), 2.19 (s, 3H), 7.04 (d, 1H, J=1.4 Hz), 7.21 (d, 1H, J=5.2Hz), 7.48 (d, 2H, J=8.8 Hz), 7.52 (dd, 1H, J=8.8 Hz, 2.4 Hz), 7.77-7.83(m, 3H), 8.64 (d, 1H, J=5.2 Hz), 8.71 (s, 1H), 10.75 (s, 1H). MS: m/z443.0 (M⁺+1).

Example 46 Synthesis ofN-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide

[0259]

[0260] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 116 mg of(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 122 mg of4-Trifluoromethyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ7.31 (d, 1H, J=2.8 Hz), 7.36 (m, 2H), 7.54-7.59 (m, 2H), 7.73 (d, 1H,J=8.0 Hz), 7.77 (d, 1H, J=9.2 Hz), 7.97 (d, 1H, J=8.0 Hz), 8.00 (s, 1H),8.82 (dd, 2H, J=6.0 Hz, 1.2 Hz), 10.16 (s, 1H). MS: m/z 441.8 (M⁺+1).

Example 47 Synthesis of4-tert-Butyl-N-[4,5-difluoro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

[0261]

[0262] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 117 mg of(2-Amino-4,5-difluoro-phenyl)-pyridin-4-yl-methanone and 116 mg of4-tert-butyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 1.28(s, 9H), 7.17 (t, 1H, J=8.4 Hz), 7.45 (d, 2H, J=8.4 Hz), 7.54 (d, 2H,J=4.4 Hz), 7.64 (dd, 1H, J=11.6 Hz, 6.8 Hz), 7.72 (d, 2H, J=8.4 Hz),8.85 (d, 2H, J=5.2 Hz), 10.42 (s, 1H). MS: m/z 431.1 (M⁺+1).

Example 48 Synthesis of4-tert-Butyl-N-[4-chloro-2-(6-morpholin-4-yl-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide

[0263]

[0264] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 158 mg of(2-Amino-5-chloro-phenyl)-(6-morpholin-4-yl-pyridin-3-yl)-methanone and116 mg of 4-tert-butyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz,CDCl₃): δ 1.22 (s, 3H), 3.76 (t, 4H, J=4.6 Hz), 3.857 (t, 4H, J=4.6H),8.78 (d, 1H, J=9.2 Hz), 7.30 (m, 2H), 7.34 (m, 1H), 7.46 (m, 1H),7.54-7.56 (m, 3H), 7.99 (d, 1H, J=9.2 Hz), 8.16 (v, 1H), 9.29 (s, 1H).MS: m/z 515.1 (M⁺+1).

Example 49 Synthesis ofN-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-oxazol-5-yl-benzenesulfonamide

[0265]

[0266] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 123 mg of(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and 122 mgof 4-oxazol-5-yl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ2.63 (s, 3H), 7.33 (m, 2H), 7.37 (s, 1H), 7.56 (m, 3H), 7.67-7.3 (m,3H), 7.94 (m, 1H), 7.97 (s, 1H), 8.52 (b, 1H), 9.45 (s, 1H). MS: m/z454.1 (M⁺+1).

Example 50 Synthesis of4-tert-Butyl-N-[4-chloro-2-(2-methylsulfanyl-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

[0267]

[0268]4-tert-Butyl-N-[4-chloro-2-(2-chloro-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide(475 mg, 1.0 mmol) was dissolved in 10 mL dry THF and treated with solidsodium thiomethoxide (355 mg, 5 mmol) and the mixture heated at 70° C.for 16 h. The solvent was concentrated to about 2 mL and added to 5 mLcold 1M HCl. The light yellow solid precipitate was collected byfiltration and product was purified by HPLC. ¹H-NMR (400 MHz, CDCl₃): δ1.26 (s, 9H), 2.61 (s, 3H), 6.86 (d, 1H, J=5.2 Hz), 7.18 (s, 1H), 7.28(d, 1H, J=2.4 Hz), 7.39 (d, 2H, J=8.8 Hz), 7.51 (dd, 1H, J=8.8 Hz, 2.4Hz), 7.67 (m, 2H), 7.76 (d, 1H, J=8.8 Hz), 8.56 (d, 1H, J=5.2 Hz), 10.13(s, 1H). MS: m/z 476.1 (M⁺+1).

Example 51 Synthesis ofN-[4-Chloro-2-(2-methyl-pyridine-4-carbonyl)phenyl]-4-oxazol-5-yl-benzenesulfonamide

[0269]

[0270] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 123 mg of(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and 122 mgof 4-oxazol-5-yl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ2.78 (s, 3H), 7.29 (d, 1H, J=2.8 Hz), 7.45 (m, 2H), 7.48 (s, 1H), 7.55(dd, 1H, J=9.2 Hz, 2.8 Hz)), 7.67 (m, 3H), 7.83 (d, 2H, J=8.4 Hz), 8.03(s, 1H), 8.81 (d, 1H, J=5.6 Hz), 10.10 (s, 1H). MS: m/z 454.9 (M⁺+1).

Example 52 Synthesis ofN-[4-Chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-4-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide

[0271]

[0272] To a suspension of NaBH₄ (0.70 g, 18.3 mmol) in dry THF (20 mL)was added BF₃.Et₂O (0.25 mL, 20.1 mmol) drop wise at 0° C. over 5 minand the mixture was stirred for 30 min. A solution of2-methyl-2-phenyl-propionic acid (1.0 g, 6.1 mmol) in dry THF (10 mL)was added drop wise at 0° C. over 30 min, and the mixture was stirred atroom temperature for 4 h. Methanol was slowly added to the reactionmixture until hydrogen evolution stopped. The mixture was diluted with10% HCl and extracted twice with EtOAc. The organic layer was dried overNa₂SO₄ and then under vacuum to yield colorless oil.

[0273] This material was dissolved in DCM (25 mL), pyridine (1.2 mL,15.3 mmol) and acetyl chloride (2.2 mL, 30.5 mmol) added, and thereaction mixture left to stir at room temperature overnight. Thereaction mixture was washed with 10% HCl and the organic layer was driedover MgSO₄.

[0274] The material was then dissolved in DCM (25 mL) and cooled to 0°C. Chlorosulfonic acid (1.2 mL, 18 mmol) was added drop wise over 15minutes and the mixture was stirred at the same temperature for 3H. Thevolatiles were evaporated and SOCl₂ (10 mL) was added and the mixturestirred at room temperature for 3 h. The excess SOCl₂ was evaporated andthe residue was treated with ice-water and extracted with ether. Theorganic layer was washed with water and brine, dried over MgSO₄ andconcentrated in vacuo to afford the aryl sulfonyl chloride as ayellowish oil.

[0275] This oil was treated with a solution of(2-amino-5-chlorophenyl)-pyridin-4-yl-methanone (1.2 g, 5 mmol) in 10 mLpyridine and heated at 60 C for 4 h. The solvent was evaporated and theresidue suspended in 3M HCl (10 mL) and stirred at room temperature for16 h. The reaction mixture was put in an ice bath and neutralized withconcentrated NaOH solution. The white precipitate formed was collectedby filtration, washed with water and dried in vacuo and purified byflash chromatography to yield 320 mg ofN-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-(2-hydroxy-1,1-dimethylethyl)-benzenesulfonamide.

[0276] Oxidation of this intermediate with mCPBA according to thegeneral procedure gaveN-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-4-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide.¹H-NMR (400 MHz, CDCl₃): δ 1.24 (s, 6H), 3.58 (s, 2H), 7.29 (d, 1H,J=2.4 Hz), 7.37 (m, 4H), 7.53 (m, 2H), 7.62 (m, 2H), 7.78 (d, 1H, J=8.8Hz), 8.23 (d, 2H, J=6.8 Hz), 9.51 (s, 1H). MS: m/z 461.1 (M⁺+1).

Example 53 Synthesis ofN-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-4-ethyl-benzenesulfonamide

[0277]

[0278] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 116 mg of(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 102 mg of4-ethyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 0.94 (t,3H, J=7.6 Hz), 2.38 (q, 2H, J=15.2 Hz, 7.6 Hz), 6.94 (d, 2H, J=6.8 Hz),7.16 (m, 2H), 7.23 (m, 1H), 7.30 (m, 4H), 8.60 (b, 2H), 9.73 (b, 1H).MS: m/z 401.1 (M⁺+1).

Example 54 Synthesis ofN-[4-Chloro-2-(pyrimidine-2-carbonyl)-phenyl]-4-oxazol-5-yl-benzenesulfonamide

[0279]

[0280] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 116 mg of(2-Amino-5-chloro-phenyl)-pyrimidin-2-yl-methanone and 122 mg of4-oxazol-5-yl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 7.43(s, 1H), 7.45 (m, 1H), 7.50 (m, 1H), 7.55 (m, 1H), 7.64 (m, 2H), 7.66(d, 1H, J=8.8 Hz), 7.86 (m, 2H), 7.97 (s, 1H), 8.86 (d, 2H), 10.63 (s,1H). MS: m/z 441.9 (M⁺+1).

Example 55 Synthesis ofN-[4-chloro-2-(pyrimidine-4-carbonyl)-phenyl]-4-oxazol-5-yl-benzenesulfonamide

[0281]

[0282] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 116 mg of(2-Amino-5-chloro-phenyl)-pyrimidin-4-yl-methanone and 122 mg of4-oxazol-5-yl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 7.43(s, 1H), 7.53 (dd, 1H, J=8.8 Hz, 2.4 Hz), 7.62 (m, 2H), 7.75 (m, 2H),7.80 (m, 3H), 7.98 (s, 1H), 8.99 (d, 1H, J=5.2 Hz), 9.25 (b, 1H), 10.29(b, 1H). MS: m/z 441.9 (M⁺+1).

Example 56 Synthesis ofN-[4-Chloro-2-(pyridine-3-carbonyl)-phenyl]-4-oxazol-5-yl-benzenesulfonamide

[0283]

[0284] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 116 mg of(2-Amino-5-chloro-phenyl)-pyridin-3-yl-methanone and 122 mg of4-oxazol-5-yl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 7.23(m, 2H), 7.42-7.47 (m, 3H), 7.58-7.62 (m, 3H), 7.71 (dt, 1H, J=7.6 Hz,2.0 Hz), 7.88 (s, 1H), 8.45 (b, 1H), 8.58 (bd, 1H, J=3.6 Hz), 9.67 (s,1H). MS: m/z 458.1 (M⁺+1)

Example 57 Synthesis of4-tert-Butyl-N-[4-chloro-2-(pyridine-2-carbonyl)-phenyl]-benzenesulfonamide

[0285]

[0286] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 116 mg of(2-Amino-5-chloro-phenyl)-pyridin-2-yl-methanone and 116 mg of4-tert-Butyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 1.24(s, 9H), 7.34-7.38 (m, 2H), 7.47 (dd, 1H, J=8.8 Hz, 2.4 Hz), 7.60 (m,1H), 7.65-7.68 (m, 4H), 7.85 (d, 1H, J=8 Hz), 8.00 (td, 1H, J=7.6 Hz, 2Hz), 8.71 (bd, 1H, J=4.8 Hz). MS: m/z 429.9 (M⁺+1).

Example 58 Synthesis ofN-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-(1,1-dimethyl-propyl)-benzenesulfonamide

[0287]

[0288] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 116 mg of(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 123 mg of4-(1,1-dimethyl-propyl)-benzenesulfonyl chloride. ¹H-NMR (400 MHz,CDCl₃): δ 0.59 (t, 3H, J=7.2 Hz), 1.23 (s, 6H), 1.61 (q, 2H, J=7.2 Hz),7.28 (d, 1H, J=2.8 Hz), 7.36 (m, 2H), 7.53 (m, 3H), 7.67-7.74 (m, 3H),8.84 (m, 2H), 10.14 (s, 1H). MS: m/z 443.9 (M⁺+1).

Example 59 Synthesis of4-tert-butyl-N-[4-chloro-2-(2-chloro-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

[0289]

[0290] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 133 mg of(2-Amino-5-chloro-phenyl)-(2-chloro-pyridin-4-yl)-methanone and 116 mgof 4-tert-Butyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ1.26 (s, 9H), 7.18 (dd, 5.2 Hz, 1.6 Hz), 7.25 (m, 1H), 7.32 (m, 1H),7.41 (d, 2H, J=6.4 Hz), 7.54 (dd, 1H, J=9.2 Hz, 2.4 Hz), 7.67 (m, 2H),7.77 (d, 1H, J-8.8 Hz), 8.55 (d, 1H, J=5.2 Hz), 10.09 (s, 1H). MS: m/z463.0 (M⁺+1).

Example 60 Synthesis ofN-[4-Chloro-2-(6-methyl-pyridine-2-carbonyl)-phenyl]-4-oxazol-5-yl-benzenesulfonamide

[0291]

[0292] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 123 mg of(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-2-yl)-methanone and 122 mgof 4-oxazol-5-yl-benzenesulfonyl chloride ¹H-NMR (400 MHz, CDCl₃): δ2.67 (s, 3H), 7.46-7.50 (m, 4H), 7.61-7.70 (m, 4H), 7.65 (m, 2H),7.94-8.00 (m, 1H), 8.15 (s, 1H). MS: m/z 454.0 (M⁺+1).

Example 61 Synthesis of4-tert-Butyl-N-[4-chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

[0293]

[0294] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 123 mg of(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and 116 mgof 4-tert-Butyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ1.26 (s, 9H), 2.63 (s, 3H) 7.29 (d, 1H, J=2.8 Hz), 7.45-7.55 (m, 3H),7.67 (m, 2H), 7.83 (m, 2H), 8.03 (s, 1H), 8.81 (d, 1H, J=5.6 Hz), 10.10(s, 1H). MS: m/z 443.9 (M⁺+1).

Example 62 Synthesis4-tert-Butyl-N-[4-chloro-2-(2-methyl-1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

[0295]

[0296] The title compound was prepared according to the generalprocedure by mCPBA oxidation of4-tert-butyl-N-[4-chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide.¹H-NMR (400 MHz, CDCl₃): δ 1.26 (s, 9H), 2.63 (s, 3H) 7.29 (d, 1H, J=2.8Hz), 7.50-7.57 (m, 3H), 7.67 (m, 2H), 7.87 (m, 2H), 8.24 (s, 1H), 8.89(d, 1H, J=5.6 Hz), 10.31 (s, 1H). MS:m/z 459.0 (M⁺+1)

Example 63 Synthesis of4-tert-Butyl-N-[4-chloro-2-(6-methylsulfanyl-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide

[0297]

[0298]4-tert-Butyl-N-[4-chloro-2-(6-chloro-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide(231 mg, 0.5 mmol) was dissolved in dry THF (5 mL) and treated withsodium thiomethoxide (175 mg, 2.5 mmol) and the mixture was heated at70° C. for 4 h. The solvent was evaporated and the residue suspended inwater (5 mL) and the product was precipitated by the drop wise additionof 3M HCl and purified by HPLC. ¹H-NMR (400 MHz, CDCl₃): δ 1.19 (s, 9H),2.60 (s, 3H), 7.21-7.28 (m, 3H), 7.31 (m, 1H), 7.50-7.54 (m, 3H), 7.65(dd, 1H, J=8.4 Hz, 2.4 Hz), 7.78 (d, 1H, J=8.8 Hz), 8.19 (m, 1H), 9.62(s, 1H). MS: m/z 476.0 (M⁺+1).

Example 64 Synthesis of4-tert-Butyl-N-[4-chloro-2-(6-methanesulfonyl-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide

[0299]

[0300]4-tert-Butyl-N-[4-chloro-2-(6-methylsulfanyl-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide(48 mg, 0.1 mmol) and mCPBA (35 mg, 0.2 mmol) were dissolved in DCM (4mL) and the mixture stirred at room temperature overnight. The solventwas evaporated and product was purified by HPLC. ¹H-NMR (400 MHz,CDCl₃): δ 1.25 (s, 9H), 3.30 (s, 3H), 7.27 (m, 1H), 7.38 (m, 2H), 7.56(dd, 1H, J=8.8 Hz, 2.8 Hz), 7.66 (m, 2H), 7.80 (d, 1H, J=8.8 Hz), 8.04(dd, 1H, J=8 Hz, 2 Hz), 8.18 (d, 1H, J=8.0 Hz), 8.61 (m, 1H), 10.00 (s,1H). MS: m/z 508.0 (M⁺+1).

Example 65 Synthesis of4-tert-Butyl-N-[3,4-difluoro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

[0301]

[0302] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 117 mg of(6-Amino-2,3-difluoro-phenyl)-pyridin-4-yl-methanone and 116 mg of4-tert-Butyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 1.22(s, 9H), 7.31 (d, 2H, J=8.4 Hz), 7.40-7.47 (m, 3H), 7.55 (d, 2H, J=8.4Hz), 7.59 (m, 1H), 8.69 (b, 1H), 8.82 (d, 2H, J=6.0 Hz). MS: m/z 431.0(M⁺+1).

Example 66 Synthesis of4-tert-Butyl-N-[4-chloro-2-(pyrazine-2-carbonyl)-phenyl]-benzenesulfonamide

[0303]

[0304] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 117 mg of(2-Amino-5-chloro-phenyl)-pyrazin-2-yl-methanone and 116 mg of4-tert-butyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 1.24(s, 9H), 7.38 (dm, 2H, J=6.8 Hz), 7.50 (dd, 1H, J=9.2 Hz, 1.6 Hz), 7.70(m, 2H), 7.76 (m, 1H), 7.80 (m, 1H), 8.62 (m, 1H), 8.77 (m, 1H), 9.06(m, 1H), 10.37 (s, 1H). MS: m/z 430.0 (M⁺+1).

Example 67 Synthesis ofN-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonamide

[0305]

[0306] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 116 mg of(2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 117 mg of4-Isopropoxy-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 1.01(d, 6H, J=5.6 Hz), 4.27 (m, 1H), 6.51 (d, 2H, J=8.8 Hz), 6.87 (d, 1H,J=8.8 Hz), 7.15-7.25 (m, 4H), 7.60 (d, 2H, J=6.0 Hz), 8.64 (d, 2H, J=6Hz), 9.60 (s, 1H). MS: m/z 431.9 (M⁺+1).

Example 68 Synthesis ofN-[4-Bromo-2-(pyridine-4-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonamide

[0307]

[0308] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 138 mg of(2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 117 mg of4-Isopropoxy-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 1.31(d, 6H, J=6 Hz), 4.49 (q, 1H, J=6.0 Hz), 6.73 (d, 2H, J=6.8 Hz), 7.39(m, 3H), 7.63-7.70 (m, 4H), 8.82 (d, 2H, J=6.0 Hz), 9.99 (s, 1H). MS:m/z476.0 (M⁺+1)

Example 69 Synthesis ofN-[4-Bromo-2-(pyridine-4-carbonyl)-phenyl]-4-ethyl-benzenesulfonamide

[0309]

[0310] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 138 mg of(2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 102 mg of4-ethyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ 1.19 (t,3H, J=7.6 Hz), 2.62 (q, 2H, J=7.6 Hz), 7.20 (d, 2H, J=8.8 Hz, 7.38 (m,3H), 7.65-7.72 (m, 4H), 8.81 (d, 2H, 6.4 Hz), 10.06 (s, 1H). MS: m/z446.0 (M⁺+1).

Example 70 Synthesis ofN-[4-Bromo-2-(pyridine-4-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide

[0311]

[0312] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 138 mg of(2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 130 mg of4-Trifluoromethoxy-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ7.23 (d, 2H, J=8.0 Hz), 7.45 (m, 3H), 7.71 (m, 2H), 7.85 (d, 2H, J=8.8Hz), 8.85 (d, 2H, J=6.4 Hz), 10.23 (s, 1H). MS: m/z 502.9 (M⁺+1).

Example 71 Synthesis of4-tert-Butyl-N-[4-chloro-2-(2-cyano-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

[0313]

[0314] Dimethyl sulfate (126 mg, 1 mmol) and4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide(445 mg, 1 mmol) were dissolved in dry THF (5 mL). The reaction mixturewas stirred at room temperature for 1 hour and at 60° C. for two hours.After cooling to room temperature, to the solution was added 25% (w/v)aqueous KCN solution (5 mL) and the mixture stirred for 16 h. Thesolvent was evaporated in vacuo and the product was purified by HPLC.¹H-NMR (400 MHz, CDCl₃): δ 1.27 (s, 9H), 7.22 (d, 1H, J=2.0 Hz),7.41-7.47 (m, 3H), 7.56 (dd, 1H, J=2.4 Hz), 7.69 (m, 3H), 7.79 (d, 1H,J=9.2 Hz), 8.87 (d, 1H, J=5.2 Hz), 10.06 (s, 1H). MS: m/z 454.0 (M⁺+1).

Example 72 Synthesis of4-tert-Butyl-N-[4-chloro-2-(2-methanesulfonyl-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

[0315]

[0316]4-tert-Butyl-N-[4-chloro-2-(2-chloro-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide(232 mg, 0.5 mmol) was dissolved in dry THF (5 mL) and treated withsodium thiomethoxide (175 mg, 2.5 mmol) and the mixture was heated at70° C. for 16 h. The solvent was evaporated and the residue suspended inwater (5 mL) and the product was precipitated by the drop wise additionof 3M HCl. The precipitate was collected by filtration, dissolved in DCM(10 mL) and treated with mCPBA (172 mg, 1 mmol). After stirring at roomtemperature for 16 h, the DCM solution was washed with saturated NaHCO₃solution (10 mL). The organic layer was washed with water, dried and thesolvent was evaporated. The product was purified by HPLC to give whitepowder after lyophilization. ¹H-NMR (400 MHz, CDCl₃): δ 1.28 (s, 9H),3.30 (s, 3H), 7.24 (d, 1H, J=2.4 Hz), 7.45 (d, 2H, J=8.0 Hz), 7.48 (m,1H), 7.54 (dd, 1H, J=8.8 Hz, 2.4 Hz), 7.74 (d, 2H, J=8.0 Hz), 7.78 (d,1H, J=8.8 Hz), 8.87 (d, 1H, J=5.2 Hz), 10.23 (s, 1H). MS: m/z 507.0(M⁺+1).

Example 73 Synthesis ofN-[4-Bromo-2-(pyridine-4-carbonyl)-phenyl]-4-methanesulfonyl-benzenesulfonamide

[0317]

[0318] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 138 mg of (2-Amino-5-bromo-phenyl)-phenyl-methanone and127 mg of 4-Methanesulfonyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz,CDCl₃): δ 3.07 (s, 3H), 7.45 (d, 1H, J=2.0 Hz), 7.49 (d, 2H, J=6.0 Hz),7.15 (m, 3H), 8.00 (s, 4H), 8.89 (d, 2H, J=6.0 Hz), 10.32 (b, 1H). MS:m/z 496.9.0 (M⁺+1).

Example 74 Synthesis of4-Acetyl-N-[4-bromo-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

[0319]

[0320] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using 138 mg of (2-Amino-5-bromo-phenyl)-phenyl-methanone and109 mg of 4-acetyl-benzenesulfonyl chloride. ¹H-NMR (400 MHz, CDCl₃): δ2.59 (s, 3H), 7.44 (d, 1H, J=2.0 Hz), 7.56 (d, 2H, J=6.4 Hz, 7.64-7.71(m, 2H), 7.90 (d, 2H, J=8.8 Hz), 7.97 (d, 2H, J=8.8 Hz), 8.88 (d, 2H,J=6.4 Hz), 10.24 (b, 1H). MS: m/z 459.8 (M⁺+1).

Example 75 Synthesis of4-tert-Butyl-N-[4-chloro-2-(6-methyl-pyridine-2-carbonyl)-phenyl]-benzenesulfonamide

[0321]

[0322] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-2-yl)-methanone and4-tert-Butyl-benzenesulfonyl chloride and purified by HPLC. ¹H NMR: δ1.29 (s, 9H), 2.94 (s, 3H), 7.42-7.46 (m, 3H), 7.51 (d, J=8.8 Hz, 1H),7.58 (d, J=2.0 Hz, 1H), 7.62 (d, J=7.2 Hz, 1H), 7.66 (d, J=6.8 Hz, 1H),7.74 (d, J=8.0 Hz, 1H), 8.1 (bs, 1H). MS: M/z 443.1 (M⁺+1).

Example 76 Synthesis of4-tert-Butyl-N-[4-chloro-2-(6-chloro-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide

[0323]

[0324] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using(2-Amino-5-chloro-phenyl)-(6-chloro-pyridin-3-yl)-methanone and4-tert-butyl-benzenesulfonyl chloride and purified by HPLC. ¹H NMR: δ1.21 (s, 9H), 7.30 (d, J=2.4 Hz, 1H), 7.33 (d, J=6.6 Hz, 2H), 7.43 (d,J=8.0 Hz, 1H), 7.52 & 7.55 (dd, J=8.8 Hz, 2.8 Hz, 1H), 7.60 (d, J=7.0Hz, 1H), 7.79 (m, 3H), 8.27 (d, J=2.0 Hz, 1H), 9.73 (s, 1H). MS: M/z463.0 (M⁺+1).

Example 77 Synthesis ofN-[4-Chloro-2-(pyridine-3-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide

[0325]

[0326] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using (2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone and4-Trifluoromethoxy-benzenesulfonyl chloride and purified by HPLC. ¹HNMR: δ 6.93 (d, J=8.0 Hz, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.58-7.61 (m,3H), 7.67 (d, J=8.8 Hz, 2H), 8.03-8.05 (m, 1H), 8.74 (d, J=1.6 Hz, 1H),8.79 & 8.80 (dd, J=6.0 Hz, 1.6 Hz, 1H), 9.73 (s, 1H). MS: M/z 456.9(M⁺+1).

Example 78 Synthesis ofN-[4-Chloro-2-(pyridine-3-carbonyl)-phenyl]-4-methanesulfonyl-benzenesulfonamide

[0327]

[0328] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using (2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone and4-Methanesulfonyl-benzenesulfonyl chloride and purified by HPLC. ¹H NMR(CDCl₃): δ 3.01 (s, 3H), 7.36-7.37 (d, J=2.4 Hz, 1H), 7.43 (m, 1H), 7.54& 7.57 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.70-7.73 (m, 1H), 7.77 (d, J=8.8 Hz,1H), 7.90 (m, 4H), 8.59 (d, J=2.0 Hz, 1H), 8.80 & 8.82 (dd, J=4.8 Hz,1.6 Hz, 1H), 9.98 (s, 1H). MS: M/z 450.9 (M⁺+1).

Example 79 Synthesis ofN-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide

[0329]

[0330] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and4-Trifluoromethoxy-benzenesulfonyl chloride and purified by HPLC. ¹H NMR(DMSO-d₆): δ 6.90 (d, J=8.4 Hz, 1H), 7.50 (d, J=8.8 Hz, 2H), 7.49-7.61(m, 4H), 7.66 (d, J=8.8 Hz, 2H), 8.81 (d, J=4.8 Hz, 2H), 10.26 (s, 1H).MS: M/z 456.9 (M⁺+1).

Example 80 Synthesis ofN-[4-Chloro-2-(pyridine-3-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonamide

[0331]

[0332] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using (2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone and4-isopropoxy-benzenesulfonyl chloride and purified by HPLC. ¹H NMR(CDCl₃): δ 1.19 (s, 3H), 1.20 (s, 3H), 4.35-4.38 (m, 1H), 6.63 (d, J=9.2Hz, 2H), 7.24 (m, 2H), 7.35-7.38 (m, 1H), 7.43 (d, J=2.4 Hz, 1H),7.45-7.49 (m, 2H), 7.62 (d, J=8.8 Hz, 1H), 7.70-7.73 (m, 1H), 8.51 (bs,1H), 8.68 (bs, 1H), MS: M/z=431.0 (M⁺+1).

Example 81 Synthesis of4-Acetyl-N-[4-chloro-2-(1-oxy-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide

[0333]

[0334] The title compound was prepared by the mCPBA oxidation of4-Acetyl-N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-benzenesulfonamideaccording to the general procedure.

Example 82 Synthesis ofN-[4-Chloro-2-(1-oxy-pyridine-3-carbonyl)-phenyl]-4-methanesulfonyl-benzenesulfonamide

[0335]

[0336] The title compound was prepared by the mCPBA oxidation of4-methanesufonyl-N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-benzenesulfonamideaccording to the general procedure. ¹H NMR (DMSO-d6): δ 3.27 (s, 3H),6.90 (d, J=8.8 Hz, 1H), 7.47 & 7.49 (dd, J=8.0 Hz, 1.2 Hz, 1H),7.51-7.55 (m, 1H), 7.56 & 7.58 (dd, J=8.0 Hz, 2.4 Hz, 1H), 7.62 (d,J=2.0 Hz, 1H), 7.79 (d, J=7.6 Hz, 2H), 8.05 (d, J=8.8 Hz, 2H), 8.19 (d,J=2.0 Hz, 1H), 8.41 & 8.42 (dd, J=6.8 Hz, 1.2 Hz, 1H), 10.46 (s, 1H).MS: M/z 467.0 (M⁺+1).

Example 83 Synthesis of4-Chloro-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

[0337]

[0338] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and4-chloro-benzenesulfonyl chloride and purified by HPLC. ¹H NMR (CDCl₃):δ 7.20 (dd, 2H, J=4.4 Hz, 2.0), 7.31 (m, 2H), 7.53 (dd, 1H, J=8.8 Hz,2.8 Hz), 7.65 (m, 2H), 7.76 (d, 1H, J=8.8 Hz), 8.79 (dd, 2H, J=4.4 Hz,1.6 Hz), 10.00 (s, 1H). MS: m/z 407.1 (M⁺+1).

Example 84 Synthesis of4-tert-Butyl-N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-benzenesulfonamide

[0339]

[0340] To (2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone (150 mg, 0.64mmol) dissolved in 750 uL pyridine was added 4-tert-butylbenzenesulfonylchloride (225 mg, 0.97 mmol) and the mixture stirred at 60° C.overnight. The reaction mixture was diluted with 1.0 mL H₂O and theprecipitate formed was collected by vacuum filtration. The crude productwas recrystallized from EtOAc/hexane yielding 190 mg of pure titlecompound. 1H NMR (CDCl3) δ 9.87 (s, 1H), 8.79 (d, J=4.8 Hz, 1H), 8.52(s, 1H), 7.79 (d, J=8.8 Hz, 2H), 7.61 (d, J=8.8 Hz, 2H), 7.52 (dd, J=8.8Hz, 2.4 Hz, 1H), 7.40 (dd, J=7.6 Hz, 4.8 Hz, 1H), 7.33-7.31 (m, 3H),1.22 (s, 9H). MS: m/z=429.0 (M⁺+1).

Example 85 Synthesis of4-tert-Butyl-N-[4-chloro-2-(1-oxy-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide

[0341]

[0342] The title compound was prepared by the mCPBA oxidation of4-tert-Butyl-N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-benzenesulfonamideaccording to the general procedure and purified by HPLC. 1H NMR (CDCl3)δ 9.71 (s, 1H) 8.56 (d, J=7.6 Hz, 1H) 8.43 (s, 1H) 7.71-7.66 (m, 4H)7.61-7.53 (m, 2H) 7.44-7.38 (m, 3H) 1.28 (s, 9H). MS (ES) m/z=445.0(M⁺+1).

Example 86 Synthesis ofN-[4-Chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide

[0343]

[0344] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and4-trifluoromethoxy-benzenesulfonyl chloride and purified by HPLC. 1H NMR(CDCl3) δ 10.17 (s, 1H) 8.63 (d, J=4 Hz, 1H) 7.78 (m, 3H) 7.51 (s, 1H)7.30 (s, 1H) 7.17 (s, 1H) 7.09 (s, 1H) 6.97 (d, J=4 Hz, 2H) 2.64 (s,3H). MS (ES) m/z=471.0 (M⁺+1).

Example 87 Synthesis ofN-[4-Chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonamide

[0345]

[0346] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and4-isopropoxy-benzenesulfonyl chloride and purified by HPLC. 1H NMR(CDCl3) δ 9.94 (s, 1H) 8.61 (d, J=5 Hz, 1H) 7.78 (d, J=8.8, 1H) 7.61 (d,J=8 Hz, 1H) 7.50 (dd, J=11 Hz, 2 Hz, 2H) 7.27 (d, J=2.4 Hz, 1H) 7.07 (s,1H) 6.96 (d, J=4 Hz, 1H) 6.75 (d, J=8.8 Hz, 2H) 4.47 (m, 1H) 2.63 (s,3H) 1.27 (s, 6H). MS (ES) m/z=445.0 (M⁺+1).

Example 88 Synthesis of4-Acetyl-N-[4-chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide

[0347]

[0348] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and4-acetyl-benzenesulfonyl chloride and purified by HPLC. 1H NMR (CDCl3) δ8.50 (d, J=4.8 Hz, 1H) 7.67-7.25 (m, 5H) 7.20-6.85 (m, 4H) 2.52 (s, 3H)2.45 (s, 3H). MS: (ES) m/z=429.0 (M⁺+1).

Example 89 Synthesis ofN-[4-Chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-4-methanesulfonyl-benzenesulfonamide

[0349]

[0350] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and4-methanesulfonyl-benzenesulfonyl chloride and purified by HPLC. 1H NMR(CDCl3) δ 10.38 (s, 1H) 8.64 (s 1H) 7.95 (s, 4H) 7.72 (s, 1H) 7.51 (s,1H) 7.31 (s, 1H) 7.11 (s, 1H) 6.99 (s, 1H) 3.04 (s, 3H) 2.64 (s, 3H).MS: (ES) m/z=464.9 (M⁺+1).

Example 90 Synthesis of3-{4-[4-Chloro-2-(2-methyl-pyridine-4-carbonyl)-phenylsulfamoyl]-phenyl}-propionicacid methyl ester

[0351]

[0352] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and3-(4-chlorosulfonyl-phenyl)-propionic acid methyl ester and purified byHPLC. 1H NMR (CDCl3) δ 10.13 (s, 1H) 8.62 (d, J=4.8 Hz, 1H) 7.73 (d,J=8.8 Hz, 1H) 7.65 (d, J=8.8 Hz, 2H) 7.49 (dd, J=8.8 Hz, 2.4 Hz, 1H)7.28 (d, J=2.4 Hz, 1H) 7.19 (d, J=12 Hz, 2H) 7.13 (s, 1H) 6.95 (d, J=4.8Hz, 1H) 3.62 (s, 3H) 2.90 (t, J=8 Hz, 2H) 2.63 (s, 3H) 2.56 (t, J=8 Hz,2H). MS: m/z=473.0 (M⁺+1).

Example 91 Synthesis ofN-[4-Chloro-2-(2-methyl-1-oxy-pyridine-4-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide

[0353]

[0354] The title compound was prepared by the mCPBA oxidation ofN-[4-Chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamideaccording to the general procedure and purified by HPLC. 1H NMR (CDCl3)δ 9.66 (s, 1H) 8.26 (d, J=6.8 Hz, 1H) 7.89 (d, 2H, J=8.4 Hz) 7.85 (s,1H) 7.81 (d, 2H, J=8.4 Hz) 7.73 (d, 1H, J=8.8 Hz) 7.54 (dd, 1H, J=12 Hz,2 Hz) 7.36 (t, 1H, J=5.6 Hz, 3.2 Hz) 7.24-7.19 (m, 1H) 2.55 (s, 3H). MS(ES) m/z=486.9 (M⁺+1).

Example 92 Synthesis ofN-[4-Chloro-2-(2-methyl-1-oxy-pyridine-4-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonamide

[0355]

[0356] The title compound was prepared by the mCPBA oxidation ofN-[4-Chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonamideaccording to the general procedure and purified by HPLC. 1H NMR (CDCl3)δ 9.39 (s, 1H) 8.32 (d, J=6.8 Hz, 1H) 7.75 (d, J=11.2, 1H) 7.57-7.52 (m,3H) 7.36 (d, J=2.4 Hz, 1H) 7.30 (d, J=2.4 Hz, 1H) 7.21 (dd, J=7.2 Hz,2.8 Hz, 1H) 6.71 (d, J=7.2 Hz, 2H) 4.46 (p, J=6.0 Hz, 1H) 2.57 (s, 3H)1.29 (d, J=5.6 Hz, 6H). MS (ES) m/z=461.0 (M++1).

Example 93 Synthesis ofN-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-iodo-benzenesulfonamide

[0357]

[0358] To a magnetically stirred mixture of precursor amino-ketone (2.32g, 10.0 mmol) in dry pyridine (20 mL) was added a solution of pipsylchloride (4.78 g, 15.8 mmol) in toluene (20 mL) under dry nitrogen. Theaddition was performed over a 2 h period. The reaction was stirredovernight at 50° C., then additional pipsyl chloride (850 mg), as asolution in toluene, was added. After 6 h, the reaction was concentratedand the residue was taken up in ethyl acetate. The organic layer waswashed with water, then the mixture was filtered. The layers wereseparated and the organic layer was dried (MgSO₄), filtered andconcentrated to provide crystalline material. ¹H-NMR (CDCl3) δ 9.95 (brs, 1H, NH), 8.82 (dm, 2H, J=5.2 Hz), 7.76 (d, 1H, J=8.8 Hz), 7.54 (dm,1H, J=8.8 Hz, J=2.6 Hz), 7.41 (dm, 2H, J=8.8 Hz), 7.30 (d, 1H, J=2.6Hz), 7.30 (d, 1H, J=2.6 Hz), 7.19 (dm, 2H, J=5.2 Hz). MS: m/z 499 (M+1).

Example 94 Synthesis ofN-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-(2,4-dimethyl-oxazol-5-yl)-benzenesulfonamide

[0359]

[0360] Trifluoromethanesulfonic acid (4.5 mmol) was added to a stirredsolution of iodobenzene diacetate (0.39 g, 1.2 mmol) in acetonitrile (10mL) and stirred at ambient temperature for 20 minutes. To this reactionpropiophenone (1.0 mmol) was added and the reaction was refluxed for 2.5h. After completion of the reaction, as judged by TLC, excessacetonitrile was evaporated and the crude product was extracted intodichloromethane (3×40 mL). The combined organic extracts were thenwashed with saturated aqueous sodium bicarbonate (2×50 mL), dried(MgSO4), filtered and concentrated to give a dark amber waxy solid. Theproduct was purified by column chromatography on silica gel using ethylacetate-hexane (5:95, 10:90) to furnish a crystalline solid.

[0361] 2,4-dimethyl-5-phenyloxazole (53 mg, 0.31 mmol) was treated withchlorosulfonic acid (3.0 equivalents) in dry dichloromethane (8 mL) at0° C. The solution was allowed to slowly warm to room temperature andmonitored by LC/MS for complete reaction, then the reaction was washedwith cold water. The organic layer was dried over magnesium sulfate,filtered and concentrated.

[0362] The residue was treated with thionyl chloride (2 equivalents) indry dichloromethane (5 mL). The desired product was isolated byconcentration of the reaction mixture to give4-(2,4-dimethyl-oxazol-5-yl)benzenesulfonyl chloride, which was usedimmediately in the next step: mass spectrum m/z 272 (M+1);

[0363] To a magnetically stirred solution of the aminoketone (1.62 g,7.0 mmol) in dry pyridine (30 mL) was added drop wise a solution of thesulfonyl chloride in 1.0 mL of dichloromethane and the slightly turbidreaction was stirred at ambient temperature. After 5 h, the reaction wasdiluted with ethyl acetate (25 mL) and washed with cold 3M HCl, followedby washing with aqueous NaHCO₃, then washed with water. The organiclayer was dried (MgSO4), filtered and concentrated to give a pale yellowwaxy solid. The product was purified by preparative hplc and purematerial lyophilized to give the desired product. ¹H NMR (CDCl3) δ 8.84(br s, 2H), 7.69 (dm, 2H, J=8.4 Hz), 7.65 (d, 1H, J=8.8 Hz), 7.46 (dm,1H, J=2.2 Hz), 7.43 (dm, 2H, J=8.4 Hz), 7.36 (ddd, 1H, J=8.8 Hz, J=2.6Hz, J=0.7 Hz), 7.24 (2H, obscured), 7.15 (br s, 1H), 3.19 (s, 3H), 3.13(s, 3H). MS: m/z 468 (M+1).

Example 95 Synthesis of4-tert-Butyl-N-[4-chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide

[0364]

[0365] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone (243 mg, 1.0mmol) and 4-tert-Butyl-benzenesulfonyl chloride (232 mg, 1.0 mmol) andpurified by HPLC. ¹H NMR (CDCl3) δ 10.71 (br s, 1H, NH), 8.63 (dd, 1H,J=5.1 Hz, J=1.6 Hz), 7.83 (d, 1H, J=8.8 Hz), 7.73 (dm, 2H, J=8.4 Hz),7.49 (dd, 1H, J=8.8 Hz, J=2.6 Hz), 7.43 (dm, 2H, J=8.5 Hz), 7.27 (dd,1H, J=9.5 Hz, J=1.8 Hz), 7.18 (dd, 1H, J=7.7 Hz, J=4.8 Hz), 7.13 (d, 1H,J=2.6 Hz), 2.29 (s, 3H), 1.29 (s, 9H). MS: m/z 443 (M+1).

Example 96 Synthesis of4-tert-Butyl-N-[4-chloro-2-(2-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide

[0366]

[0367] The title compound was prepared by the mCPBA oxidation of4-tert-Butyl-N-[4-chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-benzenesulfonamideaccording to the general procedure. ¹H NMR (CDCl₃) δ 10.71 (br s, 1H,NH), 8.62 (dm, 1H, J=5.9 Hz), 7.81 (d, 1H, J=9.1 Hz), 7.78 (dm, 2H,J=8.4 Hz), 7.54 (dd, 1H, J=8.8 Hz, J=2.6 Hz), 7.48 (dm, 2H, J=8.4 Hz),7.44 (m, 2H), 7.18 (d, 1H, J=2.6 Hz), 2.32 (s, 3H), 1.32 (s, 9H). MS:m/z 459 (M+1).

Example 97 Synthesis ofN-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonamide

[0368]

[0369] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using(2-amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and4-isopropoxy-benzenesulfonyl chloride and purified by HPLC. ¹H NMR(CDCl3) δ 10.63 (br s, 1H, NH), 8.63 (dd, 1H, J=4.8 Hz, J=1.8 Hz), 7.79(d, 1H, J=8.8 Hz), 7.71 (d, 1H, J=8.8 Hz), 7.48 (dd, 1H, J=9.0 Hz, J=2.2Hz), 7.27 (dd, 1H, J=7.7 Hz, J=1.8 Hz), 7.19 (dd, 1H, J=7.7 Hz, J=4.8Hz), 7.14 (d, 1H, J=2.2 Hz), 4.55 (septet, 1H, J=6 Hz), 2.35 (s, 3H),1.35 (d, 3H, J=6 Hz). MS: m/z 445 (M+1).

Example 98 Synthesis ofN-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide

[0370]

[0371] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using (2amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and4-trifluoromethoxy-benzenesulfonyl chloride and purified by HPLC.

[0372]¹H NMR (CDCl3) δ 10.76 (br s, 1H, NH), 8.65 (dd, 1H, J=4.8 Hz,J=2.0 Hz), 7.88 (dm, 2H, J=8.8 Hz), 7.80 (d, H1, J=9.2 Hz), 7.52 (dd,1H, J=9.0 Hz, J=2.2 Hz), 7.1-7.3 (m, 4H), 7.18 (d, 1H, J=2.6 Hz), 2.35(s, 3H). MS: m/z 471 (M+1).

Example 99 Synthesis of4-Acetyl-N-[4-chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide

[0373]

[0374] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using (2amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and4-acetyl-benzenesulfonyl chloride and purified by HPLC. ¹H NMR (CDCl3) δ10.79 (br s, 1H, NH), 8.65 (dd, 1H, J=4.8 Hz, J=1.8 Hz), 7.98 (d, 2H,J=8.8 Hz), 7.92 (d, 2H, J=8.8 Hz), 7.79 (d, 1H, J=9.2 Hz), 7.50 (dd, 1H,J=9.0 Hz, J=2.2 Hz), 7.22 (dd, 1H, J=7.7 Hz, J=1.5 Hz), 7.16 (m, 2H),2.60 (s, 3H), 2.36 (s, 3H). MS: m/z 429 (M+1).

Example 100 Synthesis ofN-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-4-methanesulfonyl-benzenesulfonamide

[0375]

[0376] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using (2amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and4-methanesulfonyll-benzenesulfonyl chloride and purified by HPLC. ¹H NMR(CDCl3) δ 10.86 (br s, 1, NH), 8.65 (dd, 1H, J=4.8 Hz, J=1.8 Hz), 8.02(m, 4H), 7.78 (d, 1H, J=8.8 Hz), 7.53 (dd, 1H, J=8.8 Hz, J=2.6 Hz),7.1-7.3 (m, 3H), 3.07 (s, 3H), 2.41 (s, 3H). MS: m/z 465 (M+1).

Example 101 Synthesis of3-{4-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenylsulfamoyl]-phenyl}-propionicacid methyl ester

[0377]

[0378] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using (2amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)methanone and3-(4-Chlorosulfonyl-phenyl)-propionic acid methyl ester and purified byHPLC. ¹H-NMR (CDCl3) δ 10.75 (br s, 1H, NH), 8.64 (dm, 1H, J=4.8 Hz),7.79 (dd, 1H, J=9.2 Hz, J=1.1 Hz), 7.75 (d, 2H, J=7.3 Hz), 7.49 (dm, 1H,J=9.2 Hz), 7.1-7.3 (m, 5H), 3.65 (s, 3H), 2.97 (t, 2H, J=7.6 Hz), 2.61(t, 2H, J=7.6 Hz), 2.35 (s, 3H). MS: m/z 473 (M+1).

Example 102 Synthesis ofN-[4-Chloro-2-(2-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide

[0379]

[0380] The title compound was prepared by the mCPBA oxidation ofN-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]4-trifluoromethoxy-benzenesulfonamideaccording to the general procedure. ¹H NMR (CDCl3) δ 10.68 (br s, 1H,NH), 8.54 (dm, 1H, J=6.6 Hz), 7.92 (dm, 2H, J=8.8 Hz), 7.78 (d, 1, J=8.8Hz), 7.56 (dd, 1, J=8.8 Hz, J=2.2 Hz), 7.45-7.15 (m, 4), 7.18 (d, 1,J=2.6 Hz), 2.33 (s, 3H). MS: m/z 487 (M+1).

Example 103 Synthesis ofN-[4-Chloro-2-(2-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonamide

[0381]

[0382] The title compound was prepared by the mCPBA oxidation ofN-[4-chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]4-isopropoxy-benzenesulfonamideaccording to the general procedure. ¹H NMR (CDCl3) δ 10.56 (br s, 1H,NH), 8.56 (dm, 1H, J=6.6 Hz), 7.79 (d, 1H, J=8.8 Hz), 7.75 (d, 2H, J=8.8Hz), 7.53 (dd, 1H, J=8.8 Hz, J=2.6 Hz), 7.39 (t, 1H, J=7.2 Hz), 7.21 (d,1H, J=8.0 Hz), 7.17 (d, 1H, J=2.6 Hz), 6.87 (d, 2H, J=8.8 Hz), 4.58(septet, 1H, J=6 Hz), 2.32 (s, 3H), 1.35 (d, 3H, J=6 Hz). MS: m/z 461(M+1).

Example 104 Synthesis of4-Acetyl-N-[4-chloro-2-(2-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide

[0383]

[0384] The title compound was prepared by the mCPBA oxidation of4-Acetyl-N-[4-chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-benzenesulfonamideaccording to the general procedure. ¹H NMR (CDCl3) δ 10.7 (br s, 1H,NH), 8.54 (d, 1H, J=6.6 Hz), 8.02 (d, 2H, J=8.4 Hz), 7.95 (d, 2H, J=8.4Hz), 7.76 (d, 1H, J=8.8 Hz), 7.54 (dd, 1H, J=8.8 Hz, J=2.2 Hz), 7.38 (m,1H), 7.22 (d, 1H, J=2.6 Hz), 7.16 (dm, 1H, J=7.7 Hz), 2.62 (s, 3H), 2.33(s, 3H). MS: m/z 445 (M+1).

Example 105 Synthesis ofN-[4-Chloro-2-(2-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-4-methanesulfonyl-benzenesulfonamide

[0385]

[0386] The title compound was prepared by the mCPBA oxidation ofN-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-4-methanesulfonyl-benzenesulfonamideaccording to the general procedure. ¹H NMR (CDCl3) δ 10.78 (br s, 1H,NH), 8.38 (dm, 1H, J=6.6 Hz), 8.05 (s, 4H), 7.76 (d, 1H, J=8.8 Hz), 7.55(dd, 1H, J=8.8 Hz, J=2.2 Hz), 7.25 (m, 1H), 7.22 (d, 1H, J=2.2 Hz), 6.76(dm, 1H, J=7.7 Hz), 3.09 (s, 3H), 2.32 (s, 3H). MS: m/z 481 (M+1).

Example 106 Synthesis of3-{4-[4-Chloro-2-(2-methyl-1-oxy-pyridine-3-carbonyl)-phenylsulfamoyl]-phenyl}-propionicacid methyl ester

[0387]

[0388] The title compound was prepared by the mCPBA oxidation of3-{4-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenylsulfamoyl]-phenyl}-propionicacid methyl ester according to the general procedure. ¹H NMR (CDCl3) δ10.66 (br s, 1H, NH), 8.54 (dm, 1H, J=6.2 Hz), 7.78 (m, 3H), 7.52 (dd,1H, J=8.8 Hz, J=2.2 Hz), 7.39 (t, 1H, J=7.2 Hz), 7.31 (d, 2H, J=8.0 Hz),7.18 (m, 2H), 3.65 (s, 3H), 2.99 (t, 2H, J=7.6 Hz), 2.64 (t, 2H, J=7.6Hz), 2.31 (s, 3H). MS: m/z 489 (M+1).

Example 107 Synthesis of4-tert-Butyl-N-[4-chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide

[0389]

[0390] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and4-tert-butyl-benzenesulfonyl chloride and purified by HPLC. ¹H NMR(CDCl₃) δ 9.77 (br s, 1H, NH), 8.40 (dm, 1H, J=1.8 Hz), 7.77 (dm, 1H,J=8.6 Hz), 7.71 (dd, 1H, J=8.1 Hz, J=2.2 Hz), 7.58 (dm, 2H, J=8.6 Hz),7.50 (dd, 1H, J=9.0 Hz, J=2.4 Hz), 7.32 (d, 1H, J=2.2 Hz), 7.29 (dm, 2H,J=8.6 Hz), 7.23 (d, 1H, J=8.1 Hz), 2.63 (s, 3H), 1.20 (s, 9H). MS: m/z443 (M+1).

Example 108 Synthesis of4-tert-Butyl-N-[4-chloro-2-(6-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide

[0391]

[0392] The title compound was prepared by the mCPBA oxidation of4-tert-butyl-N-[4-chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-benzenesulfonamideaccording to the general procedure. ¹H NMR (CDCl₃) δ 9.64 (br s, 1H,NH), 8.47 (m, 1H), 7.68 (d, 1H, J=8.8 Hz), 7.66 (d, 2H, J=8.8 Hz), 7.64(m, 1H), 7.53 (m, 2H), 7.41 (d, 1H, J=2.2 Hz), 7.40 (d, 2H, J=8.8 Hz),2.69 (s, 3H), 1.26 (s, 9H). MS: m/z 459 (M+1).

Example 109 Synthesis ofN-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide

[0393]

[0394] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)methanone and4-trifluoromethyl-benzenesulfonyl chloride and purified by HPLC. ¹H-NMR(CDCl3) δ 9.76 (br s, 1, NH), 8.50 (d, 1H, J=2.2 Hz), 7.76 (d, 1H,J=8.8), 7.73 (d, 2H, J=9.2), 7.66 (dd, 1H, J=8.0, J=2.2), 7.54 (ddm, 1H,J=8.8 Hz, J=2.6 Hz), 7.37 (d, 1H, J=2.6), 7.24 (d, 1H, J=6 Hz), 7.10 (d,2H, J=8.8 Hz), 2.35 (s, 3). MS: m/z 471 (M+1).

Example 110 Synthesis ofN-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonamide

[0395]

[0396] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)methanone and4-isopropoxy-benzenesulfonyl chloride and purified by HPLC. ¹H NMR(CDCl₃) δ 9.67 (br s, 1H, NH), 8.45 (d, 1H, J=1.8 Hz), 7.75 (d, 1H,J=8.8 Hz), 7.68 (dd, 1H, J=8.0 Hz, J=2.2 Hz), 7.55 (d, 2H, J=9.0 Hz),7.50 (dd, 1H, J=8.8 Hz, J=2.6 Hz), 7.32 (d, 1H, J=2.6 Hz), 7.24 (d, 1H,J=8.0 Hz), 6.68 (d, 2H, J=9.0 Hz), 4.43 (septet, 1H, J=6 Hz), 2.65 (s,3H), 1.28 (d, 3H, J=6 Hz). MS: m/z 445 (M+1).

Example 111 Synthesis of4-Acetyl-N-[4-chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide

[0397]

[0398] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and4-acetyl-benzenesulfonyl chloride and purified by HPLC. ¹H NMR (CDCl₃) δ9.54 (br s, 1, NH), 8.30 (m, 1), 7.77 (d, 2, J=8.8 Hz), 7.71 (d, 2,J=8.8 Hz), 7.69 (m, 1), 7.54 (dd, 1, J=8.8 Hz, J=2.2 Hz), 7.33 (d, 1,J=2.2 Hz), 7.26 (m, 1), 7.21 (d, 1, J=8.0 Hz), 2.63 (s, 3), 2.52 (s, 3).MS: m/z 429 (M+1).

Example 112 Synthesis ofN-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-methanesulfonyl-benzenesulfonamide

[0399]

[0400] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and4-Methanesulfonyl-benzenesulfonyl chloride and purified by HPLC. ¹H NMR(CDCl₃) δ 9.77 (br s, 1H, NH), 8.44 (dm, 1H, J=2.2 Hz), 7.87 (d, 2H,J=8.8 Hz), 7.83 (d, 2H, J=8.8 Hz), 7.76 (d, 1H, J=8.8 Hz), 7.60 (dd, 1H,J=8.0 Hz, J=2.2 Hz), 7.55 (dd, 1H, J=8.8 Hz, J=2.2 Hz), 7.36 (d, 1H,J=2.2), 7.26 (d, 1H, J=8.0 Hz), 3.00 (s, 3H), 2.66 (s, 3H). MS: m/z 465(M+1).

Example 113 Synthesis of3{4-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenylsulfamoyl]-phenyl}-propionicacid methyl ester

[0401]

[0402] The title compound was prepared according to the generalprocedure for the synthesis of N-Aryl-benzenesulfonamides previouslydescribed using(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and3-(4-Chlorosulfonyl-phenyl)-propionic acid methyl ester and purified byHPLC. ¹H NMR (CDCl3) δ 9.66 (br s, 1H, NH), 8.34 (d, 1H, J=2.2 Hz), 7.75(d, 1H, J=8.8 Hz), 7.72 (d, 1H, J=8.0 Hz, J=2.2 Hz), 7.56 (d, 2H, J=8.4Hz), 7.51 (dd, 1H, J=8.8 Hz, J=2.2 Hz), 7.32 (d 1H, J=2.2 Hz), 7.26 (d,1H, J=7 Hz), 7.09 (d, 2H, J=8.4 Hz), 3.65 (s, 3H), 2.97 (t, 2H, J=7.6Hz), 2.66 (s, 3H), 2.51 (t, 2H, J=7.6 Hz). MS: m/z 473 (M+1).

Example 114 Synthesis ofN-[4-Chloro-2-(6-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide

[0403]

[0404] The title compound was prepared by the mCPBA oxidation ofN-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulfonamideaccording to the general procedure. ¹H NMR (CDCl3) δ 9.60 (br s, 1, NH),8.42 (m, 1H), 7.78 (dm, 2H, J=8.4 Hz), 7.70 (dm, 1H, J=8.8 Hz), 7.56(dd, 1H, J=8.0 Hz, J=2.2 Hz), 7.44 (d, 1H, J=8.0 Hz), 7.41 (d, 1H, J=2.2Hz), 7.38 (dm, 1H, J=8.0 Hz), 7.20 (dm, 2H, J=8.4 Hz), 2.65 (s, 3H). MS:m/z 487 (M+1).

Example 115 Synthesis ofN-[4-Chloro-2-(6-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonamide

[0405]

[0406] The title compound was prepared by the mCPBA oxidation ofN-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]4-isopropoxy-benzenesulfonamideaccording to the general procedure. ¹H-NMR (CDCl₃) δ 9.53 (br s, 1H,NH), 8.25 (dm, 1H, J=1.5 Hz), 7.74 (d, 1H, J=8.8 Hz), 7.59 (dm, 2H,J=8.8 Hz), 7.52 (dd, 1H, J=8.8 Hz, J=2.6 Hz), 7.24 (d, 1H, J=8.0 Hz),7.33 (d, 1H, J=2.6 Hz), 7.20 (dd, 1H, J=8.0 Hz, J=1.6 Hz), 6.75 (dm, 2H,J=8.8 Hz), 4.51 (septet, 1H, J=6 Hz), 2.59 (s, 3H), 1.30 (d, 3H, J=6Hz). MS: m/z 461 (M+1).

Example 116 Synthesis of4-Acetyl-N-[4-chloro-2-(6-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide

[0407]

[0408] The title compound was prepared by the mCPBA oxidation of4-Acetyl-N-[4-chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-benzenesulfonamideaccording to the general procedure. ¹H-NMR (CDCl3) δ 9.16 (br s, 1H,NH), 8.15 (dm, 1H, J=2.0 Hz), 7.83 (d, 2H, J=8.1 Hz), 7.71 (d, 2H, J=8.1Hz), 7.71-7.67 (m, 2H), 7.58 (dd, 1H, J=8.8 Hz, J=2.2 Hz), 7.52 (d, 1H,J=8.4 Hz), 7.37 (d, 1H, J=2.2 Hz), 2.66 (s, 3H), 2.60 (s, 3H). MS: m/z445 (M+1).

Example 117 Synthesis ofN-[4-Chloro-2-(6-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-4-methanesulfonyl-benzenesulfonamide

[0409]

[0410] The title compound was prepared by the mCPBA oxidation ofN-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]4-methanesulfonyl-benzenesulfonamideaccording to the general procedure. ¹H-NMR (CDCl3) δ 9.39 (br s, 1H,NH), 8.61 (m, 1H), 7.88 (m, 4H), 7.68 (d, 1H, J=8.8 Hz), 7.60 (m, 2H),7.40 (m, 2H), 3.03 (s, 3H), 2.69 (s, 3H). m/z 481 (M+1)

Example 118 Synthesis of3-{4-[4-Chloro-2-(6-methyl-1-oxy-pyridine-3-carbonyl)-phenylsulfamoyl]-phenyl}-propionicacid methyl ester

[0411]

[0412] The title compound was prepared by the mCPBA oxidation of3-{4-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenylsulfamoyl]-phenyl}-propionicacid methyl ester according to the general procedure. ¹H-NMR (CDCl3) δ9.47 (br s, 1H, NH), 8.26 (m, 1H), 7.69 (d, 1H, J=8.8 Hz), 7.59 (dm, 2H,J=8.4 Hz), 7.53 (dd, 1H, J=8.8 Hz, J=2.6 Hz), 7.48 (m, 2H), 7.35 (d, 1H,J=2.6 Hz), 7.18 (dm, 2H, J=8.4 Hz), 3.64 (s, 3H), 2.88 (t, 2H, J=7.6Hz), 2.67 (s, 3H), 2.51 (t, 2H, J=7.6 Hz). MS: m/z 489 (M+1).

[0413] Measuring Efficacy of CCR9 Modulators

[0414] In Vitro Assays

[0415] A variety of assays can be used to evaluate the compoundsprovided herein, including signaling assays, migration assays, and otherassays of cellular response. CCR9 receptor signaling assays can be usedto measure the ability of a compound, such as a potential CCR9antagonist, to block CCR9 ligand-(e.g. TECK)-induced signaling. Amigration assay can be used to measure the ability of a compound ofinterest, such as a possible CCR9 antagonist, to block CCR9-mediatedcell migration in vitro. The latter is believed to resemblechemokine-induced cell migration in vivo.

[0416] In a suitable assay, a CCR9 protein (whether isolated orrecombinant) is used which has at least one property, activity, orfunctional characteristic of a mammalian CCR9 protein. The property canbe a binding property (to, for example, a ligand or inhibitor), asignaling activity (e.g., activation of a mammalian G protein, inductionof rapid and transient increase in the concentration of cytosolic freecalcium [Ca⁺⁺]), cellular response function (e.g., stimulation ofchemotaxis or inflammatory mediator release by leukocytes), and thelike.

[0417] The assay can be a cell based assay that utilizes cells stably ortransiently transfected with a vector or expression cassette having anucleic acid sequence which encodes the CCR9 receptor. The cells aremaintained under conditions appropriate for expression of the receptorand are contacted with a putative agent under conditions appropriate forbinding to occur. Binding can be detected using standard techniques. Forexample, the extent of binding can be determined relative to a suitablecontrol (for example, relative to background in the absence of aputative agent, or relative to a known ligand). Optionally, a cellularfraction, such as a membrane fraction, containing the receptor can beused in lieu of whole cells.

[0418] Detection of binding or complex formation can be detecteddirectly or indirectly. For example, the putative agent can be labeledwith a suitable label (e.g., fluorescent label, chemiluminescent label,isotope label, enzyme label, and the like) and binding can be determinedby detection of the label. Specific and/or competitive binding can beassessed by competition or displacement studies, using unlabeled agentor a ligand (e.g., TECK) as a competitor.

[0419] Binding inhibition assays can be used to evaluate the presentcompounds. In these assays, the compounds are evaluated as inhibitors ofligand binding using, for example, TECK. In this embodiment, the CCR9receptor is contacted with a ligand such as TECK and a measure of ligandbinding is made. The receptor is then contacted with a test agent in thepresence of a ligand (e.g., TECK) and a second measurement of binding ismade. A reduction in the extent of ligand binding is indicative ofinhibition of binding by the test agent. The binding inhibition assayscan be carried out using whole cells which express CCR9, or a membranefraction from cells which express CCR9.

[0420] The binding of a G protein coupled receptor by, for example, anagonist, can result in a signaling event by the receptor. Accordingly,signaling assays can also be used to evaluate the compounds of thepresent invention and induction of signaling function by an agent can bemonitored using any suitable method. For example, G protein activity,such as hydrolysis of GTP to GDP, or later signaling events triggered byreceptor binding can be assayed by known methods (see, for example,PCT/US97/15915; Neote, et al., Cell, 72:415425 (1993); Van Riper, etal., J. Exp. Med., 177:851-856 (1993) and Dahinden, et al., J. Exp.Med., 179:751-756 (1994)).

[0421] Chemotaxis assays can also be used to assess receptor functionand evaluate the compounds provided herein. These assays are based onthe functional migration of cells in vitro or in vivo induced by anagent, and can be used to assess the binding and/or effect on chemotaxisof ligands, inhibitors, or agonists. A variety of chemotaxis assays areknown in the art, and any suitable assay can be used to evaluate thecompounds of the present invention. Examples of suitable assays includethose described in PCT/US97/15915; Springer, et al., WO 94/20142; Bermanet al., Immunol. Invest., 17:625-677 (1988); and Kavanaugh et al., J.Immunol., 146:4149-4156 (1991)).

[0422] Calcium signaling assays measure calcium concentration over time,preferably before and after receptor binding. These assays can be usedto quantify the generation of a receptor signaling mediator, Ca⁺⁺,following receptor binding (or absence thereof). These assays are usefulin determining the ability of a compound, such as those of the presentinvention, to generate the receptor signaling mediator by binding to areceptor of interest. Also, these assays are useful in determining theability of a compound, such as those of the present invention, toinhibit generation of the receptor signaling mediator by interferingwith binding between a receptor of interest and a ligand.

[0423] In calcium signaling assays used to determine the ability of acompound to interfere with binding between CCR9 and a known CCR9 ligand,CCR9-expressing cells (such as a T cell line MOLT-4 cells) are firstincubated with a compound of interest, such as a potential CCR9antagonist, at increasing concentrations. The cell number can be from10⁵ to 5×10⁵ cells per well in a 96-well microtiter plate. Theconcentration of the compound being tested may range from 0 to 100 uM.After a period of incubation (which can range from 5 to 60 minutes), thetreated cells are placed in a Fluorometric Imaging Plate Reader (FLIPR®)(available from Molecular Devices Corp., Sunnyvale, Calif.) according tothe manufacturer's instruction. The FLIPR system is well known to thoseskilled in the art as a standard method of performing assays. The cellsare then stimulated with an appropriate amount of the CCR9 ligand TECK(e.g. 5-100 nM final concentration) and the signal of intracellularcalcium increase (also called calcium flux) is recorded. The efficacy ofa compound as an inhibitor of binding between CCR9 and the ligand can becalculated as an IC50 (the concentration needed to cause 50% inhibitionin signaling) or IC90 (at 90% inhibition).

[0424] In vitro cell migration assays can be performed (but are notlimited to this format) using the 96-well microchamber (calledChemoTX™). The ChemoTX system is well known to those skilled in the artas a type of chemotactic/cell migration instrument. In this assay,CCR9-expressing cells (such as MOLT-4) are first incubated with acompound of interest, such as a possible CCR9 antagonist, at increasingconcentrations. Typically, fifty thousand cells per well are used, butthe amount can range from 10³-10⁶ cells per well. CCR9 ligand TECK,typically at 50 nM (but can range from 5-100 nM), is placed at the lowerchamber and the migration apparatus is assembled. Twenty microliters oftest compound-treated cells are then placed onto the membrane. Migrationis allowed to take place at 37 C for a period of time, typically 2.5hours. At the end of the incubation, the number of cells that migratedacross the membrane into the lower chamber is then quantified. Theefficacy of a compound as an inhibitor of CCR9-mediated cell migrationis calculated as an IC50 (the concentration needed to reduce cellmigration by 50%) or IC90 (for 90% inhibition).

[0425] In Vivo Efficacy Models for Human IBD

[0426] T cell infiltration into the small intestine and colon have beenlinked to the pathogenesis of human inflammatory bowel diseases whichinclude Coeliac disease, Crohn's disease and ulcerative colitis.Blocking trafficking of relevant T cell populations to the intestine isbelieved to be an effective approach to treat human IBD. CCR9 isexpressed on gut-homing T cells in peripheral blood, elevated inpatients with small bowel inflammation such as Crohn's disease andCoeliac disease. CCR9 ligand TECK is expressed in the small intestine.It is thus believed that this ligand-receptor pair plays a role in IBDdevelopment by mediating migration of T cells to the intestine. Severalanimal models exist and can be used for evaluating compounds ofinterest, such as potential CCR9 antagonists, for an ability to affectsuch T cell migration and/or condition or disease, which might allowefficacy predictions of antagonists in humans.

[0427] Animal Models with Pathology Similar to Human Ulcerative Colitis

[0428] A murine model described by Panwala and coworkers (Panwala, etal., J. Immunol., 161(10):573344 (1998)) involves genetic deletion ofthe murine multi-drug resistant gene (MDR). MDR knockout mice (MDR−/−)are susceptible to developing a severe, spontaneous intestinalinflammation when maintained under specific pathogen-free facilityconditions. The intestinal inflammation seen in MDR−/− mice has apathology similar to that of human inflammatory bowel disease (IBD) andis defined by Th1 type T cells infiltration into the lamina propria ofthe large intestine.

[0429] Another murine model was described by Davidson et al., J ExpMed., 184(1):241-51(1986). In this model, the murine IL-10 gene wasdeleted and mice rendered deficient in the production of interleukin 10(IL-10−/−). These mice develop a chronic inflammatory bowel disease(IBD) that predominates in the colon and shares histopathologicalfeatures with human IBD.

[0430] Another murine model for IBD has been described by Powrie et al.,Int Immunol., 5(11):1461-71 (1993), in which a subset of CD4+ T cells(called CD45RB(high)) from immunocompetent mice are purified andadoptively transferred into immunodeficient mice (such as C.B-17 scidmice). The animal restored with the CD45RBhighCD4+ T cell populationdeveloped a lethal wasting disease with severe mononuclear cellinfiltrates in the colon, pathologically similar with human IBD.

[0431] Murine Models with Pathology Similar to Human Crohn's Disease

[0432] The TNF ARE(−/−) model. The role of TNF in Crohn's disease inhuman has been demonstrated more recently by success of treatment usinganti-TNF alpha antibody by Targan et al., N Engl J Med., 337(15):1029-35(1997). Mice with aberrant production of TNF-alpha due to geneticalteration in the TNF gene (ARE−/−) develop Crohn's-like inflammatorybowel diseases (see Kontoyiannis et al., Immunity, 10(3):387-98 (1999)).

[0433] The SAMP/yit model. This is model described by Kosiewicz et al.,J Clin Invest., 107(6):695-702 (2001). The mouse strain, SAMP/Yit,spontaneously develops a chronic inflammation localized to the terminalileum. The resulting ileitis is characterized by massive infiltration ofactivated T lymphocytes into the lamina propria, and bears a remarkableresemblance to human Crohn's disease.

Example 119

[0434] This example illustrates the activity associated withrepresentative compounds of the invention.

[0435] Materials and Methods (In Vitro Assays)

[0436] Reagents and Cells

[0437] MOLT-4 cells were obtained from the American Type CultureCollection (Manassas, Va.) and cultured in RPMI tissue culture mediumsupplemented with 10% fetal calf serum (FCS) in a humidified 5% CO₂incubator at 37° C. Recombinant human chemokine protein TECK wasobtained from R&D Systems (Minneapolis, Minn.). ChemoTX® chemotaxismicrochambers were purchased from Neuro Probe (Gaithersburg, Md.).CyQUANT® cell proliferation kits were purchased from Molecular Probes(Eugene, Oreg.). Calcium indicator dye Fluo-4 AM was purchased fromMolecular Devices (Mountain View, Calif.).

[0438] Conventional Migration Assay

[0439] Conventional migration assay was used to determine the efficacyof potential receptor antagonists in blocking migration mediated throughCCR9. This assay was routinely performed using the ChemoTX® microchambersystem with a 5-μm pore-sized polycarbonate membrane. To begin such anassay, MOLT-4 cells were harvested by centrifugation of cell suspensionat 1000 PRM on a GS-6R Beckman centrifuge. The cell pellet wasresuspended in chemotaxis buffer (HBSS with 0.1% BSA) at 5×10⁶ cells/mL.Test compounds at desired concentrations were prepared from 10 mM stocksolutions by serial dilutions in chemotaxis buffer. An equal volume ofcells and compounds were mixed and incubated at room temperature for 15minutes. Afterwards, 20 μL of the mixture was transferred onto the porusmembrane of a migration microchamber, with 29 μL of 50 nM chemokine TECKprotein placed at the lower chamber. Following a 150-minute incubationat 37° C., during which cells migrated against the chemokine gradient,the assay was terminated by removing the cell drops from atop thefilter. To quantify cells migrated across the membrane, 5 μL of 7×CyQUANT® solution was added to each well in the lower chamber, and thefluorescence signal measured on a Spectrafluor Plus fluorescence platereader (TECAN, Durham, N.C.). The degree of inhibition was determined bycomparing migration signals betweeen compound-treated and untreatedcells. IC50 calculation was further performed by non-linear squaresregression analysis using Graphpad Prism (Graphpad Software, San Diego,Calif.).

[0440] RAM Assay

[0441] The primary screen to identify CCR9 antagonists was carried outusing RAM assay (WO 02101350), which detects potential hits by theirability to activate cell migration under inhibitory TECK concentration.To begin such an assay, MOLT-4 cells were harvested by centrifugation ofcell suspension at 1000 RPM on a GS-6R Beckman centrifuge. The cellpellet was resuspended in chemotaxis buffer (HBSS/0.1% BSA) at 5×10⁶cells/mL. Twenty-five microliters of cells was mixed with an equalvolume of a test compound diluted to 20 μM in the same buffer. Twentymicroliters of the mixture was transferred onto the filter in the upperchemotaxis chamber, with 29 μL of 500 nM chemokine protein TECK placedin the lower chamber. Following a 150-minute incubation at 37° C., theassay was terminated by removing the cell drops from atop the filter. Toquantify cells migrated across the membrane, 5 μL of 7× CyQUANT®solution was added to each well in the lower chamber, and thefluorescence signal measured on a Spectrafluor Plus fluorescence platereader (TECAN, Durham, N.C.).

[0442] For selection of potential hits, the level of migrationactivation was calculated as a RAM index—the ratio between the signal ofa particular well and the median signal of the whole plate. Compoundswith a RAM index of greater than 1.8 were regarded as RAM positive, andwere selected for IC₅₀ determinations in conventional functional assays.

[0443] Calcium Flux Assay

[0444] Calcium flux assay measures an increase in intracellular calciumfollowing ligand-induced receptor activation. In the screen of CCR9antagonists, it was used as a secondary assay carried out on a FLIPR®machine (Molecular Devices, Mountain View, Calif.). To begin an assay,MOLT-4 cells were harvested by centrifugation of cell suspension, andresuspended to 1.5×10⁶ cells/mL in HBSS (with 1% fetal calf serum).Cells were then labeled with a calcium indicator dye Fluo-4 AM for 45minutes at 37° C. with gentle shaking. Following incubation, cells werepelletted, washed once with HBSS and resuspended in the same buffer at adensity of 1.6×10⁶ cells/mL. One hundred microliters of labeled cellswere mixed with 10 μL of test compound at the appropriate concentrationson an assay plate. Chemokine protein TECK was added at a finalconcentration of 25 nM to activate the receptor. The degree ofinhibition was determined by comparing calcium signals betweencompound-treated and untreated cells. IC50 calculations were furtherperformed by non-linear squares regression analysis using Graphpad Prism(Graphpad Software, San Diego, Calif.).

[0445] Discovery of CCR9 Antagonists

[0446] The discovery of CCR9 antagonists was carried out in two steps:First, RAM assay was used to screen a compound library in ahigh-throughput manner. The assay detected compounds by their ability tocause a positive migration signal under RAM condition. Secondly, RAMpositive compounds were tested to determine their IC₅₀s using theconventional migration and calcium flux assays.

[0447] For instance, in a screen of approximately 100,000 compounds,2000 individual wells representing approximately 2% of total compoundsshowed a RAM index greater than 1.8. These compounds were cheery-pickedand retested in duplicate wells by RAM assay. A total of 270 compounds,or 0.27% of the library, were confirmed RAM positives.

[0448] Since a RAM positive signal indicates only the presence of areceptor antagonist and not how strongly it blocks receptor functions,the RAM positive compounds were further tested for potency in calciumflux assay using MOLT-4 cells. IC₅₀ determinations on this subsetdiscovered several compounds with IC₅₀'s less than 1 μM and that did notinhibit other chemokine receptors examined at significant levels.

[0449] In Vivo Efficacy Studies

[0450] The MDR1a-knockout mice, which lack the P-glycoprotein gene,spontaneously develop colitis under specific pathogen-free condition.The pathology in these animals has been characterized as Th1-type Tcell-mediated inflammation similar to ulcerative colitis in humans.Disease normally begins to develop at around 8-10 weeks after birth.However the ages at which disease emerges and the ultimate penetrancelevel often vary considerably among different animal facilities.

[0451] In a study using the MDR1a-knockout mice, the CCR9 antagonistshown below

[0452] was evaluated by prophylactic administration for its ability todelay disease onset. Female mice (n=34) were dosed with 50 mg/kg twice aday by subcutaneous injections for 14 consecutive weeks starting at age10 weeks. The study showed that the compound prevented IBD-associatedgrowth retardation. Moreover, the number of mice developing diarrhea wasalso lower among compound-treated mice (17%), compared to mice receivingvehicle alone (24%)(FIG. 1).

[0453] In the table below, structures and activity are provided forrepresentative compounds described herein. Activity is provided asfollows for either or both of the chemotaxis assay and/or calciummobilization assays, described above: +1000 nM<IC₅₀<1 000 nM; ++, 100nM<IC₅₀<1000 nM; and +++, IC₅₀<100 nM. TABLE 1 Compounds with activityin either or both of the chemotaxis assay and calcium mobilizationassays, with IC₅₀ < 100 nM (+++)

[0454] TABLE 2 Compounds with activity in either or both of thechemotaxis assay and calcium mobilization assays, with 100 nM < IC₅₀ <1000 nM (++)

[0455] TABLE 3 Compounds with activity in either or both of thechemotaxis assay and calcium mobilization assays, with 1000 nM < IC₅₀ <10000 nM

We claim:
 1. A compound of the formula (I), or a salt thereof:

where X represents from 1 to 4 substituents independently selected fromthe group consisting of halogen, —CN, —NO₂, —OH, —OR¹, —C(O)R¹, —CO₂R′,—O(CO)R¹, —C(O)NR¹R², —OC(O)NR¹R², —SR¹, —SOR¹, —SO₂R¹, —SO₂NR¹R²,—NR¹R², —NR¹C(O)R², —NR¹C(O)₂R², —NR¹SO₂R², —NR¹(CO)NR²R³, unsubstitutedor substituted C₁₋₈ alkyl, unsubstituted or substituted C₂₋₈ alkenyl,unsubstituted or substituted C₂₋₈ alkynyl, unsubstituted or substitutedC₃₋₈ cycloalkyl, unsubstituted or substituted C₆₋₁₀ aryl, unsubstitutedor substituted 5- to 10-membered heteroaryl, and unsubstituted orsubstituted 3- to 10-membered heterocyclyl; R¹, R² and R³ are eachindependently selected from the group consisting of hydrogen,unsubstituted or substituted C₁₋₆ haloalkyl, unsubstituted orsubstituted C₁₋₆ alkyl, unsubstituted or substituted C₃₋₆ cycloalkyl,unsubstituted or substituted C₂₋₆ alkenyl, unsubstituted or substitutedC₂₋₆ alkynyl, unsubstituted or substituted C₆₋₁₀ aryl, unsubstituted orsubstituted 5- to 10-membered heteroaryl, unsubstituted or substitutedaryl-C₁₋₄ alkyl, unsubstituted or substituted aryl-C₁₋₄ alkyl, andunsubstituted or substituted aryloxy-C₁₋₄ alkyl; or two of R¹, R² and R³together with the atom(s) to which they are attached, may form anunsubstituted or substituted 5-, 6- or 7-membered ring; Y representsfrom 1 to 3 substituents, each independently selected from the groupconsisting of halogen, —CN, —NO₂, —OH, —OR⁴, —C(O)R⁴, —CO₂R⁴, —SR⁴,—SOR⁴, —SO₂R⁴, and unsubstituted or substituted C₁₋₄ alkyl; R⁴ isselected from the group consisting of hydrogen, unsubstituted orsubstituted C₁₋₆ haloalkyl, unsubstituted or substituted C₁₋₆ alkyl,unsubstituted or substituted C₃₋₆ cycloalkyl, unsubstituted orsubstituted C₂₋₆ alkenyl, and unsubstituted or substituted C₂₋₆ alkynyl;L is —C(O)—, —S—, —SO— or —S(O)₂—; and Z represents either unsubstitutedor substituted monocyclic or bicyclic C₅₋₁₀ heteroaryl or unsubstitutedor substituted monocyclic or bicyclic C₃₋₁₀ heterocyclyl, with theproviso that when X is methyl, then Z is not 2-thiophene,2-(3-hydroxy-1H-indole) or 3-(1-methylpyridinium).
 2. The compound ofclaim 1, where L is —CO—.
 3. The compound of claim 2, where X representsfrom 1 to 3 substituents independently selected from the groupconsisting of halogen, —CN, —NO₂, —OH, —OR¹, —C(O)R¹, —CO₂R¹, —O(CO)R¹,—OC(O)NR¹R², —SR¹, —SOR¹, —SO₂R¹, —NR¹R², —NR¹C(O)R², —NR¹C(O)₂R²,—NR¹(CO)NR¹R², unsubstituted or substituted C₁₋₈ alkyl, unsubstituted orsubstituted C₂₋₈ alkenyl, unsubstituted or substituted C₂₋₈ alkynyl,unsubstituted or substituted C₃₋₈ cycloalkyl, unsubstituted orsubstituted C₆₋₁₀ aryl, unsubstituted or substituted 5- or 6-memberedheteroaryl, or unsubstituted or substituted 4- to 7-memberedheterocyclyl.
 4. The compound of claim 3, where X represents 1 to 3substituents independently selected from the group consisting of —NO₂,—OR¹, —C(O)R¹, —SO₂R¹, —NR¹R², unsubstituted or substituted C₁₋₈ alkyl,unsubstituted or substituted phenyl, unsubstituted or substituted 5- or6-membered heteroaryl, or unsubstituted or substituted 5- or 6-memberedheterocyclyl.
 5. The compound of claim 2, where at least one Xsubstituent is situated para to the sulfonamido bond as defined informula (I).
 6. The compound of claim 2, where X is unsubstituted C₁₋₈alkyl, unsubstituted C₃₋₈ cycloalkyl, unsubstituted C₂₋₈ alkenyl, orunsubstituted C₂₋₈ alkynyl.
 7. The compound of claim 2, where X issubstituted C₁₋₈ alkyl, substituted C₃₋₈ cycloalkyl, substituted C₂₋₈alkenyl, or substituted C₂₋₈ alkynyl, each having from 1 to 5substituents independently selected from the group consisting ofhalogen, —OH, —CN, —NO₂, ═O, —OC(O)R¹, —OR¹, —C(O)R¹, —CONR¹R²,—OC(O)NR¹R², —NR²C(O)R¹, —NR¹C(O)NR²R³, —CO₂R′, —NR¹R², —NR²CO₂R¹, —SR¹,—SOR¹, —SO₂R¹, —SO₂NR¹R², —NR¹SO₂R², unsubstituted or substituted aryl,unsubstituted or substituted heteroaryl, and unsubstituted orsubstituted heterocyclyl.
 8. The compound of claim 7, where X issubstituted C₁₋₈ alkyl or substituted C₃₋₈ cycloalkyl, each having from1 to 3 substituents independently selected from the group consisting ofhalogen, —OH, —CN, ═O, —OC(O)R¹, —OR¹, —C(O)R¹, —CONR¹R², —NR²C(O)R¹,—CO₂R¹, —NR¹R², —SR¹, —SOR¹, —SO₂R¹, —NR¹SO₂R², unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl.
 9. Thecompound of claim 8, where X is substituted C₁₋₈ alkyl, having from 1 to3 substituents independently selected from the group consisting ofhalogen, —OH, —CN, ═O, —OC(O)R¹, —OR¹, —C(O)R¹, —CONR¹R², —NR²C(O)R¹,—CO₂R¹, —NR¹R², —SO₂R¹, unsubstituted or substituted aryl, andunsubstituted or substituted heteroaryl.
 10. The compound of claim 2,where X is unsubstituted or substituted C₆₋₁₀ aryl, unsubstituted orsubstituted 5- to 10-membered heteroaryl, or unsubstituted orsubstituted 3- to 10-membered heterocyclyl, where when X is substitutedis has from 1 to 4 substituents independently selected from the groupconsisting of halogen, unsubstituted or substituted C₁₋₈ alkyl,unsubstituted or substituted C₁₋₈ haloalkyl, —CN, —NO₂, —OH, —OR¹, ═O,—OC(O)R¹, —CO₂R¹, —C(O)R¹, —CONR¹R², —OC(O)NR¹R², —NR²C(O)R¹,—NR¹C(O)NR²R³, —NR¹R², —NR²CO₂R¹, —SR¹, —SOR¹, —SO₂R¹, —SO₂NR¹R², and—NR¹SO₂R².
 11. The compound of claim 10, where X is substituted C₆₋₁₀aryl or unsubstituted or substituted 5- to 10-membered heteroaryl, wherewhen X is substituted it has from 1 to 3 substituents independentlyselected from the group consisting of halogen, —CN, —OH, —OR¹, ═O,—OC(O)R¹, —CO₂R¹, —C(O)R¹, —CONR¹R², —NR²C(O)R¹, —NR¹R², —SR¹, —SOR¹,—SO₂R′, —NR¹SO₂R², unsubstituted or substituted C₁₋₈ alkyl, and C₁₋₈unsubstituted or substituted haloalkyl.
 12. The compound of claim 11,where X is unsubstituted or substituted phenyl or unsubstituted orsubstituted 5- or 6-membered heteroaryl, where when X is substituted ithas from 1 to 3 substituents independently selected from the groupconsisting of halogen, —OH, —OR¹, —C(O)R¹, —CONR¹R², —NR²C(O)R¹, —NR¹R²,—SO₂R¹, unsubstituted or substituted C₁₋₈ alkyl, and unsubstituted orsubstituted C₁₋₈ haloalkyl.
 13. The compound of claim 10, where X isunsubstituted or substituted 4- to 7-membered heterocyclyl, where when Xis substituted it has from 1 to 3 substituents independently selectedfrom the group consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, —OR¹, —OH,—OC(O)R¹, —CO₂R¹, —C(O)R¹, —CONR¹R², —NR¹R², —SO₂R¹, and —NR¹SO₂R². 14.The compound of claim 13, where X is a unsubstituted or substituted 5-or 6-membered heterocyclyl, where when X is substituted it has 1 to 2substituents independently selected from the group consisting ofunsubstituted or substituted C₁₋₈ alkyl, unsubstituted or substitutedC₁₋₈ haloalkyl, —OR¹, —OH, —C(O)R¹, —CONR¹R², —NR¹R², and —SO₂R′. 15.The compound of claim 2, where R¹, R² and R³ are unsubstituted.
 16. Thecompound of claim 2, where R¹, R² and R³, when substituted, can havefrom 1 to 3 substituents independently selected from the groupconsisting of halogen, —OH, —OR′, —OCOHNR′, —OCONR′₂, —SH, —SR′,—SO₂NH₂, —CONH₂, —NHC(O)NH₂, NR′C(O)NH₂, —CO₂H, —CN, —NO₂, —NH₂, —NHR′and —NR′₂, —S(O)R′, —S(O)₂R′, —CO₂R′, —CONR′₂, —CONHR′, —C(O)R′,—NR′COR′, —NHCOR′, —NR′CO₂R′, —NHCO₂R′, —CO₂R′, —NR′C(O)NR′₂,—NHC(O)NR′₂, —NR′C(O)NHR′, —NHC(O)NHR′, —NR′SO₂R′, —NHSO₂R′, —SO₂NR′₂,and —SO₂NHR′, where R′ is C₁₋₆alkyl.
 17. The compound of claim 2, whereY represents from 1 to 2 substituents, each independently selected fromthe group consisting of halogen, —CN, —NO₂, —OH, —OR⁴, —C(O)R⁴, —CO₂R⁴,—SR⁴, —SOR⁴, —SO₂R⁴, and unsubstituted or substituted C₁₋₄ alkyl. 18.The compound of claim 2, where Y represents from 1 to 3 substituentsindependently selected from the group consisting of halogen, —CN, —NO₂,—OR⁴, —C(O)R⁴, —SR⁴, —CF₃, —SOR⁴, and —SO₂R⁴.
 19. The compound of claim18, where Y represents from 1 to 3 substituents independently selectedfrom the group consisting of halogen, —CN, —NO₂, —CF₃, and —SO₂R⁴. 20.The compound of claim 18, where Y represents 1 or 2 substituents whereat least halogen is present and optionally another substituent selectedfrom the group consisting of halogen, —CN, —NO₂, —OH, —OR⁴, —C(O)R⁴,—CO₂R⁴, —SR⁴, —SOR⁴, —SO₂R⁴ and unsubstituted or substituted C₁₋₄ alkyl.21. The compound of claim 2, where at least one Y substituent is locatedpara to the sulfonamide bond as defined in formula (I), and one Ysubstituent is halogen.
 22. The compound of claim 18, where Y isunsubstituted C₁₋₄ alkyl.
 23. The compound of claim 18, where Y issubstituted C₁₋₄ alkyl, having from 1 to 3 substituents independentlyselected from the group consisting of halogen, —OH, —OR⁴, —CN, —NO₂, ═O,—OC(O)R⁴, —CO₂R⁴, —C(O)R⁴, —CONR⁴R⁵, —OC(O)NR⁴R⁵, —NR⁴C(O)R⁵,—NR⁴C(O)NR⁵R⁶, —NR⁴R⁵, —NR⁴CO₂R⁵, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, and—NR⁴SO₂R⁵, where R⁴, R⁵ and R⁶ are each independently selected from thegroup consisting of hydrogen, unsubstituted or substituted C₁₋₆haloalkyl, unsubstituted or substituted C₁₋₆ alkyl, unsubstituted orsubstituted C₃₋₆ cycloalkyl, unsubstituted or substituted C₂₋₆ alkenyl,and unsubstituted or substituted C₂₋₆ alkynyl; or where any two of R⁴,R⁵ and R⁶ together with the atom(s) to which they are attached, may forma 5-, 6- or 7-membered ring.
 24. The compound of claim 23, where Y issubstituted C₁₋₄ alkyl, having from 1 to 3 substituents independentlyselected from the group consisting of halogen, —OH, —OR⁴, —CN, —NO₂, ═O,—OC(O)R⁴, —CO₂R⁴, —C(O)R⁴, —CONR⁴R⁵, —NR⁴C(O)R⁵, —NR⁴R⁵, —NR⁴, —SR⁴,—SOR⁴, —SO₂R⁴, and —NR⁴SO₂R⁵.
 25. The compound of claim 23, where R⁴, R⁵and R⁶ are unsubstituted.
 26. The compound of claim 23, where R⁴, R⁵ andR⁶, when substituted, can have from with from 1 to 3 substituentsindependently selected from the group consisting of —OH, —OR′, —SH,—SR′, —SO₂NH₂, —CONH₂, —NHC(O)NH₂, N(C₁₋₆alkyl)C(O)NH₂, —CO₂H, —CN,—NO₂, —NH₂, —NHR′, —NR′₂, —S(O)R′, —S(O)₂R′, —CO₂R′, —CONHR′, —CONR′₂,and —C(O)R′, where R′ is C₁₋₆alkyl.
 27. The compound of claim 2, where Zrepresents unsubstituted, monocyclic or bicyclic C₅₋₁₀ heteroaryl orunsubstituted, monocyclic or bicyclic C₃₋₁₀ heterocyclyl.
 28. Thecompound of claim 2, where Z is substituted, monocyclic or bicyclicC₅₋₁₀ heteroaryl or substituted, monocyclic or bicyclic C₃₋₁₀heterocyclyl, having from 1 to 5 substituents independently selectedfrom the group consisting of halogen, unsubstituted or substituted C₁₋₈alkyl, unsubstituted or substituted C₁₋₈ cycloalkyl, unsubstituted orsubstituted C₂₋₈ alkenyl, unsubstituted or substituted C₂₋₈ alkynyl,unsubstituted or substituted C₁₋₈ alkoxy, ═O, —CN, —NO₂, —OH, —OR⁷,—OC(O)R⁷, —CO₂R⁷, —C(O)R⁷, —CONR⁷R⁸, —OC(O)NR⁷R⁸, —NR⁷C(O)R⁸,—NR⁷C(O)NR⁸R⁹, —NR⁷R⁸, —NR⁷CO₂R⁸, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁷R⁸,—NR⁷SO₂R⁸, unsubstituted or substituted C₆₋₁₀ aryl, unsubstituted orsubstituted heteroaryl and unsubstituted or substituted heterocyclyl;where R⁷, R⁸ and R⁹ are each independently hydrogen, unsubstituted orsubstituted C₁₋₆ haloalkyl, unsubstituted or substituted C₁₋₆ alkyl,unsubstituted or substituted C₃₋₆ cycloalkyl, unsubstituted orsubstituted C₂₋₆ alkenyl, unsubstituted or substituted C₂₋₆ alkynyl,unsubstituted or substituted phenyl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted aryl-C₁₋₄ alkyl, andunsubstituted or substituted aryloxy-C₁₋₄ alkyl; or where any two of R⁷,R⁸ and R⁹ together with the atom(s) to which they are attached, may forma 5-, 6- or 7-membered ring.
 29. The compound of claim 2, where Zrepresents an unsubstituted 5- or 6-membered heteroaryl.
 30. Thecompound of claim 2, where Z is substituted 5- or 6-membered heteroaryl,having from 1 to 3 substituents independently selected from the groupconsisting of halogen, unsubstituted or substituted C₁₋₈ alkyl,unsubstituted or substituted C₃₋₈ cycloalkyl, unsubstituted orsubstituted C₂₋₈ alkenyl, unsubstituted or substituted C₂₋₈ alkynyl,unsubstituted or substituted C₁₋₈ alkoxy, ═O, —CN, —NO₂, —OH, —OR⁷,—OC(O)R⁷, —CO₂R⁷, —C(O)R⁷, CONR⁷R⁸, —NR⁷C(O)R⁸—NR⁷R⁸—SR⁷, —SOR⁷, —SO₂R⁷,—SO₂NR⁷R⁸, —NR⁷SO₂R⁸, unsubstituted or substituted phenyl, unsubstitutedor substituted 5- or 6-membered heteroaryl, and unsubstituted orsubstituted 3- to 7-membered heterocyclyl.
 31. The compound of claim 2,where Z represents unsubstituted or substituted 6-membered heteroarylwith carbon and up to 3 nitrogen atoms and with from 1 to 3 substituentsindependently selected from the group consisting of halogen,unsubstituted or substituted C₁₋₈ alkyl, unsubstituted or substitutedC₃₋₈ cycloalkyl, unsubstituted or substituted C₂₋₈ alkenyl,unsubstituted or substituted C₂₋₈ alkynyl, unsubstituted or substitutedC₁₋₈ alkoxy, ═O, —CN, —NO₂, —OH, —OR⁷, —OC(O)R⁷, —CO₂R⁷, —C(O)R⁷,—CONR⁷R⁸, —NR⁷C(O)R⁸, —NR⁷R⁸, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁷R⁸, —NR⁷SO₂R⁸,unsubstituted or substituted phenyl, and unsubstituted or substituted 5-and 6-membered heteroaryl.
 32. The compound of claim 2, where Z isunsubstituted or substituted 6-membered heteroaryl with carbon and 1 to2 nitrogen atoms and with 1 or 2 substituents independently selectedfrom the group consisting of halogen, unsubstituted or substituted C₁₋₆alkyl, unsubstituted or substituted C₁₋₆ alkoxy, ═O, —CN, —NO₂, —OH,—OR⁷, —C(O)R⁷, —CONR⁷R⁸, —NR⁷C(O)R⁸, —NR⁷R⁸, —SR⁷, —SOR⁷, —SO₂R⁷,—SO₂NR⁷R⁸, —NR⁷SO₂R⁸, unsubstituted or substituted 3 to 7-memberedheterocycyl, and unsubstituted or substituted 5- or 6-memberedheteroaryl.
 33. The compound of claim 2, where Z is selected from thegroup consisting of unsubstituted or substituted pyridyl, unsubstitutedor substituted pyrimidinyl, unsubstituted or substituted pyridazinyl,and unsubstituted or substituted pyrazinyl.
 34. The compound of claim33, where Z is selected from the group consisting of substitutedpyridyl, substituted pyrimidinyl, substituted pyridazinyl, andsubstituted pyrazinyl, and where at least one ring nitrogen issubstituted with ═O.
 35. The compound of claim 2, where Z is pyridinylwith from 0 to 3 substituents; pyrimidinyl with from 0 to 3substituents; pyrazinyl with from 0 to 3 substituents; or pyridazinylwith from 0 to 3 substituents.
 36. The compound of claim 2, where Z issubstituted with at least one substituent located ortho to one of theheteroatoms in the ring or directly connected to a ring heteroatom. 37.The compound of claim 28, where the substituent on Z is unsubstitutedC₁₋₈ alkyl, unsubstituted C₃₋₈ cycloalkyl, unsubstituted C₂₋₈ alkenyl,unsubstituted C₂₋₈ alkynyl or unsubstituted C₁₋₈ alkoxy, unsubstitutedC₆₋₁₀ aryl, unsubstituted 3- to 7-membered heterocyclyl, and 3- to7-membered heteraryl.
 38. The compound of claim 28, where thesubstituent on Z is substituted C₁₋₈ alkyl, substituted C₃₋₈ cycloalkyl,substituted C₂₋₈ alkenyl, substituted C₂₋₈ alkynyl or substituted C₁₋₈alkoxy, each having from 1 to 5 substituents independently selected fromthe group consisting of halogen, —OH, —OR⁷, —CN, —NO₂, ═O, —CN, —NO₂,—OC(O)R⁷, —CO₂R⁷, —C(O)R⁷, —CONR⁷R⁸, —OC(O)NR⁷R⁸—NR⁷C(O)R⁸,—NR⁷C(O)NR⁸R⁹, —NR⁷R⁸, —NR⁷CO₂R⁸, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁷R⁸,—NR⁷SO₂R⁸, unsubstituted or substituted phenyl, unsubstituted orsubstituted 5- or 6-membered heteroaryl, or unsubstituted or substituted3- to 6-membered heterocyclyl.
 39. The compound of claim 28, where thesubstituent on Z is substituted C₁₋₈ alkyl, substituted C₃₋₈ cycloalkyl,substituted C₂₋₈ alkenyl, substituted C₂₋₈ alkynyl or substituted C₁₋₈alkoxy groups, each having from 1 to 3 substituents independentlyselected from the group consisting of halogen, —OH, —OR⁷, ═O, —CO₂R⁷,—C(O)R⁷, —CONR⁷R⁸, —NR⁷C(O)R⁸, —NR⁷R⁸, —SR⁷, —SOR⁷; —SO₂R⁷—NR⁷SO₂R⁸,unsubstituted or substituted phenyl, unsubstituted or substituted 5- or6-membered heteroaryl, and unsubstituted or substituted 3- to 6-memberedheterocyclyl.
 40. The compound of claim 28, where the substituent on Zis substituted C₁₋₈ alkyl, substituted C₃₋₈ cycloalkyl, substituted C₂₋₈alkenyl, substituted C₂₋₈ alkynyl or substituted C₁₋₈ alkoxy groups,each having from 1 to 3 substituents independently selected from thegroup consisting of halogen, —OH, —OR⁷, ═O, —C(O)R⁷, —CO₂R⁷, —CONR⁷R⁸,—NR⁷C(O)R⁸, —NR⁷R⁸, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁷R⁸, —NR⁷SO₂R⁸,unsubstituted or substituted 5- or 6-membered heteroaryl, and 3- to6-membered heterocyclyl.
 41. The compound of claim 28, where thesubstituent on Z is substituted aryl, substituted heteroaryl orsubstituted heterocyclyl, each having from 1 to 5 substituentsindependently selected from the group consisting of halogen, —OH, —OR⁷,—CN, —NO₂, ═O, —CN, —NO₂, —OC(O)R⁷, —OC(O)R⁷, —CO₂R⁷, —C(O)R⁷, —CONR⁷R⁸,—OC(O)NR⁷R⁸, —NR⁷C(O)R⁸, —NR⁷C(O)NR⁸R⁹, —NR⁷R⁸, —NR⁷CO₂R⁸, —SR⁷, —SOR⁷,—SO₂R⁷, —SO₂NR⁷R⁸, —NR⁷SO₂R⁸ and unsubstituted or substituted 5- or6-membered heteroaryl, and 3- to 6-membered heterocyclyl.
 42. Thecompound of claim 28, where the substituent on Z is substituted phenylor substituted heteroaryl, each having from 1 to 3 substituentsindependently selected from the group consisting of halogen, —OH, —OR⁷,—CN, —NO₂, ═O, —CN, —NO₂, —OC(O)R⁷, —CO₂R⁷, —C(O)R⁷, —CONR⁷R⁸,—NR⁷C(O)R⁸, —NR⁷R⁸, —SR⁷, —SOR⁷, —SO₂R⁷, —NR⁷SO₂R⁸, unsubstituted orsubstituted C₁₋₈ alkyl, unsubstituted or substituted C₁₋₈ haloalkyl,unsubstituted or substituted C₃₋₈ cycloalkyl, and 3- to 6-memberedheterocyclyl.
 43. The compound of claim 28, where the substituent on Zis unsubstituted or substituted heterocyclyl having from 1 to 2substituents independently selected from the group consisting ofunsubstituted or substituted C₁₋₈ alkyl, C₁₋₈ haloalkyl, —OR⁷, —OH,—C(O)R⁷, —CONR⁷R⁸, —NR⁷R⁸, and —SO₂R⁷.
 44. The compound of claim 28,where each R⁷, R⁸ and R⁹ is unsubstituted.
 45. The compound of claim 28,where each R⁷, R⁸ and R⁹, when substituted, can have from 1 to 3substituents independently selected from the group consisting ofhalogen, —OH, —OR′, —OCONHR′, —OCONR′₂, —SH, —SR′, —CN, —SO₂NH₂, —CONH₂,—NHC(O)NH₂, —NR′C(O)NH₂, —CO₂H, —NO₂, —NH₂, —NHR′ and —NR′₂, —S(O)R′,—S(O)₂R′, —CO₂R′, —CONR′₂, —CONHR′, —C(O)R′, —NR′COR′, —NHCOR′,—NR′CO₂R′, —NHCO₂R′, —CO₂R′, —NR′C(O)NR′₂, —NHC(O)NR′₂, —NR′C(O)NHR′,—NHC(O)NHR′, —NR′SO₂R′, —NHSO₂R′, —SO₂NR′₂, and —SO₂NHR′, where R′ isC₁₋₆alkyl.
 46. The compound of claim 3, where Y represents from 1 to 3substituents, each independently selected from the group consisting ofhalogen, —CN, —NO₂, —OH, —OR⁴, —C(O)R⁴, —CO₂R⁴, —SR⁴, —SOR⁴, —SO₂R⁴, andunsubstituted or substituted C₁₋₄ alkyl.
 47. The compound of claim 3,where at least one Y is halogen.
 48. The compound of claim 46, where Xis C₁₋₈ alkyl.
 49. The compound of claim 3, where Z representsunsubstituted or substituted, monocyclic or bicyclic C₅₋₁₀ heteroaryl orunsubstituted or substituted, monocyclic or bicyclic C₃₋₁₀ heterocyclyl.50. The compound of claim 3, where Z is pyridinyl with from 0 to 3substituents; pyrimidinyl with from 0 to 3 substituents; pyrazinyl withfrom 0 to 3 substituents; or pyridazinyl with from 0 to 3 substituents.51. The compound of claim 49, where X is C₁₋₈ alkyl.
 52. The compound ofclaim 17, where Z represents unsubstituted or substituted, monocyclic orbicyclic C₅₋₁₀ heteroaryl or unsubstituted or substituted, monocyclic orbicyclic C₃₋₁₀ heterocyclyl.
 53. The compound of claim 17, where Z ispyridinyl with from 0 to 3 substituents; pyrimidinyl with from 0 to 3substituents; pyrazinyl with from 0 to 3 substituents; or pyridazinylwith from 0 to 3 substituents.
 54. The compound of claim 52, where atleast one Y is halogen.
 55. The compound of claim 46, where Z representsunsubstituted or substituted, monocyclic or bicyclic C₅₋₁₀ heteroaryl orunsubstituted or substituted, monocyclic or bicyclic C₃₋₁₀ heterocyclyl.56. The compound of claim 46, where Z is pyridinyl with from 0 to 3substituents; pyrimidinyl with from 0 to 3 substituents; pyrazinyl withfrom 0 to 3 substituents; or pyridazinyl with from 0 to 3 substituents.57. The compound of claim 56, where X is C₁₋₈ alkyl.
 58. The compound ofclaim 56, where at least one Y is halogen.
 59. The compound of claim 2,which has one of the following formulae:

where X′ and X″ are each independently selected from the groupconsisting of hydrogen, halogen, —CN, —NO₂, —OH, —OR¹, —C(O)R¹, —CO₂R′,—O(CO)R¹, —C(O)NR¹R², —OC(O)NR¹R², —SR¹, —SOR¹, —SO₂R′, —SO₂NR¹R²,—NR¹R², —NR¹C(O)R², —NR¹C(O)₂R², —NR¹SO₂R², —NR¹(CO)NR²R³, unsubstitutedor substituted C₁₋₈ alkyl, unsubstituted or substituted C₁₋₈ haloalkyl,unsubstituted or substituted C₂₋₈ alkenyl, unsubstituted or substitutedC₂₋₈ alkynyl, unsubstituted or substituted C₃₋₈ cycloalkyl,unsubstituted or substituted C₆₋₁₀ aryl, unsubstituted or substituted 5-to 10-membered heteroaryl, and unsubstituted or substituted 3- to10-membered heterocyclyl, with the proviso that X′ and X″ cannot both behydrogen simultaneously; R¹, R² and R³ are each independently selectedfrom the group consisting of hydrogen, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, 5- to 10-memberedheteroaryl, aryl-C₁₋₄ alkyl, aryl-C₁₋₄ alkyl, and aryloxy-C₁₋₄ alkyl; ortwo of R¹, R² and R³ together with the atom(s) to which they areattached, may form a 5-, 6- or 7-membered ring; Y′ and Y″ are eachindependently selected from the group consisting of hydrogen, halogen,—CN, —NO₂, —OH, —OR⁴, —C(O)R⁴, —CO₂R⁴, —SR⁴, —SOR⁴, —SO₂R⁴,unsubstituted or substituted C₁₋₄ alkyl, and unsubstituted orsubstituted C₁₋₄ haloalkyl, with the proviso that Y′ and Y″ cannot bothbe hydrogen simultaneously; R⁴ is selected from the group consisting ofhydrogen, unsubstituted or substituted C₁₋₆ haloalkyl, unsubstituted orsubstituted C₁₋₆ alkyl, unsubstituted or substituted C₃₋₆ cycloalkyl,unsubstituted or substituted C₂₋₆ alkenyl, and unsubstituted orsubstituted C₂₋₆ alkynyl; Z′ and Z″ are each independently selected fromthe group consisting of hydrogen, halogen, unsubstituted or substitutedC₁₋₈ alkyl, unsubstituted or substituted C₃₋₈ cycloalkyl, unsubstitutedor substituted C₂₋₈ alkenyl, unsubstituted or substituted C₂₋₈ alkynyl,unsubstituted or substituted C-8 alkoxy, ═O, —CN, —NO₂, —OH, —OR⁷,—OC(O)R⁷, —CO₂R⁷, —C(O)R⁷, —CONR⁷R⁸, —OC(O)NR⁷R⁸, —NR⁷C(O)R⁸,—NR⁷C(O)NR⁸R⁹, —NR⁷R⁸, —NR⁷CO₂R⁸, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁷R⁸,—NR⁷SO₂R⁸, unsubstituted or substituted C₆₋₁₀ aryl, unsubstituted orsubstituted 5- or 6-membered heteroaryl and unsubstituted or substituted3- to 7-membered heterocyclyl; and where R⁷, R⁸ and R⁹ are eachindependently hydrogen, unsubstituted or substituted C₁₋₆ haloalkyl,unsubstituted or substituted C₁₋₆ alkyl, unsubstituted or substitutedC₃₋₆ cycloalkyl, unsubstituted or substituted C₂₋₆ alkenyl,unsubstituted or substituted C₂₋₆ alkynyl, unsubstituted or substitutedphenyl, unsubstituted or substituted heteroaryl, unsubstituted orsubstituted aryl-C₁₋₄ alkyl, and unsubstituted or substitutedaryloxy-C₁₋₄ alkyl; or where any two of R⁷, R⁸ and R⁹ together with theatom(s) to which they are attached, may form a 5-, 6- or 7-memberedring.
 60. The compound of claim 59, where X′ and X″ are eachindependently selected from the group consisting of hydrogen, —NO₂,—OR¹, —C(O)R¹, —SO₂R¹, —NR¹R², unsubstituted or substituted C₁₋₈alkyl,unsubstituted or substituted C₁₋₈ haloalkyl, unsubstituted orsubstituted C₃₋₈ cycloalkyl, unsubstituted or substituted C₂₋₈ alkenyl,unsubstituted or substituted phenyl, unsubstituted or substituted 5- or6-membered heteroaryl, unsubstituted or substituted 5- or 6-memberedheterocyclyl, with the proviso that X′ and X″ cannot both be hydrogensimultaneously.
 61. The compound of claim 59, where X′ and X″ are eachindependently selected from the group consisting of hydrogen, —CF₃,—CH═CH₂, isoamyl, phenylacetylene, t-butyl, ethyl (Et), i-propyl(^(i)Pr), —C(CH₃)₂CH₂CH₃, hydroxybutyl, —C(CH₃)₂CH₂CH₂OH, —CH₂CH₂CO₂Me,—OCF₃, —OMe, —O—^(i)Pr, —C(O)Me, —SO₂Me, phenyl (Ph), —OEt, pyrazole,oxazole, and morpholinyl, with the proviso that X′ and X″ cannot both behydrogen simultaneously.
 62. The compound of claim 59, where Y′ and Y″are each independently hydrogen or halogen, with the proviso that one orboth are halogen.
 63. The compound of claim 62, where Y′ is hydrogen andY″ is chloro; Y′ and Y″ are both fluoro; Y′ is hydrogen and Y″ isfluoro; or Y′ is hydrogen and Y″ is bromo.
 64. The compound of claim 59,where at least one of Y′ or Y″ is a halogen atom and is para to thesulfonamide bond in formula (I).
 65. The compound of claim 59, where Z′and Z″ are each independently selected from the group consisting ofhydrogen, halogen, unsubstituted or substituted C₁₋₈ alkyl,unsubstituted or substituted C₁₋₈ cycloalkyl, —CN, —OH, —OR⁷, —C(O)R⁷,—CO₂R⁷, —OC(O)R⁷, —CONR⁷R⁸, —NR⁷R⁸, —NR⁷CO₂R⁸, —SR⁷, —SOR⁷, —SO₂R⁷,—NR⁷SO₂R⁸, unsubstituted or substituted C₆₋₁₀ aryl, and unsubstituted orsubstituted 5- or 6-membered heteroaryl, unsubstituted or substituted 3-to 7-membered heterocycyl.
 66. The compound of claim 59, where Z′ and Z″are each independently hydrogen, halogen, —CN, —OR⁷, —NR⁷R⁸, —SR⁷,—SOR⁷, and —SO₂R⁷, unsubstituted or substituted C₁₋₆ alkoxyl,unsubstituted or substituted C₁₋₆ alkyl, unsubstituted or substitutedphenyl, or unsubstituted or substituted 5- or 6-membered heterocyclyl.67. The compound of claim 60, where Y′ and Y″ are each independentlyhydrogen or halogen, with the proviso that one or both are halogen. 68.The compound of claim 60, where Z′ and Z″ are each independentlyselected from the group consisting of hydrogen, halogen, unsubstitutedor substituted C₁₋₈ alkyl, unsubstituted or substituted C₁₋₈ cycloalkyl,—CN, —OH, —OR⁷, —C(O)R⁷, —CO₂R⁷, —OC(O)R⁷, —CONR⁷R⁸, —NR⁷R⁸, —NR⁷CO₂R⁸,—SR⁷, —SOR⁷, —SO₂R⁷, —NR⁷SO₂R⁸, unsubstituted or substituted C₆₋₁₀ aryl,and unsubstituted or substituted 5- or 6-membered heteroaryl,unsubstituted or substituted 3- to 7-membered heterocycyl.
 69. Thecompound of claim 62, where Z′ and Z″ are each independently selectedfrom the group consisting of hydrogen, halogen, unsubstituted orsubstituted C₁₋₈ alkyl, unsubstituted or substituted C₁₋₈ cycloalkyl,—CN, —OH, —OR⁷, —C(O)R⁷, —CO₂R⁷, —OC(O)R⁷, —CONR⁷R⁸, —NR⁷R⁸, —NR⁷CO₂R⁸,—SR⁷, —SOR⁷, —SO₂R⁷, —NR⁷SO₂R⁸, unsubstituted or substituted C₆₋₁₀ aryl,and unsubstituted or substituted 5- or 6-membered heteroaryl,unsubstituted or substituted 3- to 7-membered heterocycyl.
 70. Thecompound of claim 67, where Z′ and Z″ are each independently selectedfrom the group consisting of hydrogen, halogen, unsubstituted orsubstituted C₁₋₈ alkyl, unsubstituted or substituted C₁₋₈ cycloalkyl,—CN, —OH, —OR⁷, —C(O)R⁷, —CO₂R⁷, —OC(O)R⁷, —CONR⁷R⁸, —NR⁷R⁸, —NR⁷CO₂R⁸,—SR⁷, —SOR⁷, —SO₂R⁷, —NR⁷SO₂R⁸, unsubstituted or substituted C₆₋₁₀ aryl,and unsubstituted or substituted 5- or 6-membered heteroaryl,unsubstituted or substituted 3- to 7-membered heterocycyl.
 71. Acomposition comprising a pharmaceutically acceptable carrier and acompound of claim
 2. 72. A method for treating a CCR9-mediated conditionor disease comprising administering to a subject a safe and effectiveamount of the compound of claim
 2. 73. The method of claim 72, where theCCR9-mediated disease or condition is an inflammatory condition.
 74. Themethod of claim 72, where the CCR9-mediated disease or condition is animmunoregulatory disorder.
 75. The method of claim 72, where theCCR9-mediated condition or disease is inflammatory bowel disease. 76.The method of claim 72, where the CCR9-mediated condition or disease isselected from the group consisting of an allergic disease, psoriasis,atopic dermatitis, asthma, fibrotic diseases and graft rejection. 77.The method of claim 72, where the CCR9-mediated condition or disease isselected from the group consisting of immune mediated food allergies andautoimmune diseases.
 78. The method of claim 72, where the CCR9-mediatedcondition or disease is Celiac disease or rheumatoid arthritis.
 79. Themethod of claim 72, where the administering is oral, parenteral, rectal,transdermal, sublingual, nasal or topical.
 80. The method of claim 72,where the compound is administered in combination with ananti-inflammatory or analgesic agent.
 81. A method of modulating CCR9function in a cell, comprising contacting the cell with a CCR9modulating amount of the compound of claim
 2. 82. The method of claim72, further comprising administering an anti-inflammatory or analgesicagent.
 83. The method of claim 72, where the CCR9-mediated disease orcondition is a leukemia or a solid tumor.
 84. The method of claim 72,where the CCR9-mediated disease or condition is thymoma or a thymiccarcinoma.
 85. The method of claim 72, where the CCR9-mediated diseaseor condition is acute lymphocytic leukemia.